- Email: [email protected]
Is multiple sclerosis a proresolution deficiency disorder?
Nutrition 28 (2012) 951–958
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Review
Is multiple sclerosis a proresolution deficiency disorder? Undurti N. Das MD, FAMS * UND Life Sciences, Shaker Heights, Ohio, USA School of Biotechnology, Jawaharlal Nehru Technological University, Kakinada, India Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering, Visakhapatnam, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 September 2011 Accepted 26 December 2011
The inflammatory process seen in multiple sclerosis is due to an excess production of proinflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-a, interferons, macrophage migration inhibitory factor, HMGB1 (high mobility group B1), and, possibly, a reduction in antiinflammatory cytokines IL-10, IL-4, and transforming growth factor-b that leads to increased secretion of reactive oxygen species, including nitric oxide, resulting in neuronal damage. It is suggested that failure of production of adequate amounts of resolution-inducing molecules lipoxins, resolvins, and protectins that suppress inflammation and reactive oxygen species production, enhance wound healing, and have neuroprotective properties results in inappropriate inflammation and delay in the healing/repair process, and so neuronal damage continues, as seen in multiple sclerosis. Hence, methods designed to enhance the production and/or administration of lipoxins, resolvins, and protectins may form a new approach in the prevention and treatment of multiple sclerosis and other similar autoimmune diseases. Ó 2012 Elsevier Inc. All rights reserved.
Keywords: Multiple sclerosis Inflammation Lipoxins Resolvins Protectins Free radicals Reactive oxygen species Cytokines T cells Macrophages Nitric oxide
Introduction Multiple sclerosis (MS) is an inflammatory disease of uncertain origin that leads to destruction of myelin sheaths around axons in the brain and spinal cord. Disease onset usually occurs in young adults and is more common in females. MS may not reduce lifespan but certainly erodes the quality of life of both sufferers and their families. MS presents in a variety of subtypes: i. ii. iii. iv.
Relapsing-remitting Secondary-progressive Primary-progressive Progressive-relapsing
There is no cure for MS [1]. Several antiinflammatory drugs are available to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability in relapsing MS, but none of these treatments directly act on the underlying neurodegenerative process in MS. Although genetic, environmental, and sex hormonal factors have been implicated in the * Corresponding author. Tel.: þ1 216-231-5548; fax: þ1 928-833-0316. E-mail address: [email protected] 0899-9007/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2011.12.016
pathogenesis of MS, it is known that several cytokines, nitric oxide (NO), free radicals, a deranged immune system, a deficient anti-oxidant defenses, and Toll-like receptors have a significant role in both the initiation and the perpetuation of the inflammatory process observed. It is thought that an unknown non-self-antigen mimics proteins in myelin. This antigen is presented on the surface of macrophages in combination with class 2 MHC. The resulting stimulation of Th1 T-helper lymphocytes causes their expression of lymphocyte function-associated antigen-1 and very late activation antigen-4. These T-helper cells may now bind to the cognate adhesion molecules, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, on vascular endothelial cells. The release of proteases permits the T-helper cells to cross the endothelium and enter the central nervous system. The destruction of myelin proceeds in the three following ways: Tumor necrosis factor-a (TNF-a) from Th1 lymphocytes TNF-a, oxygen free radicals, nitric oxide, and proteases from activated macrophages Antibody-mediated complement activation MS classically has been considered to be primarily a demyelinating disease in which neuronal death occurs from the early
952
U. N. Das / Nutrition 28 (2012) 951–958
stages of the disease. It is probably this process of neuronal loss that contributes to the accumulating disability in MS. The susceptibility to develop MS in a given individual seems to have at least partly a genetic basis, although this is still not very clear. Once the inflammatory process is triggered, this leads to the production of a variety of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, TNF-a, interferons (IFNs), macrophage migration inhibitory factor (MIF), high mobility group B1 (HMGB1), and possibly a reduction in the elaboration of antiinflammatory cytokines such as IL-10, IL-4, and transforming growth factor-b. This imbalance between the pro- and antiinflammatory cytokines coupled with increased secretion of free radicals such as superoxide anion (O2.), hydrogen peroxide (H2O2), singlet oxygen, inducible NO, and other reactive oxygen species by activated monocytes, macrophages, polymorphonuclear leukocytes, T cells, Kupffer cells, glial cells in the brain, and other organ-specific reticuloendothelial cells would ultimately cause target tissue/organ damage seen in MS. I propose that continued inflammatory events seen in MS could be due to failure of the resolution of inflammation. Thus, the balance between inflammation and resolution is disturbed more in favor of proinflammatory events and/or failure of resolution-inducing molecules to be produced at the most appropriate time, leading to non-resolution of inflammation. In other words, even after the inciting agent responsible for the initiation of inflammation is removed, inappropriate inflammation continues simply because resolution failed to occur. This leads to a delay in the healing/repair process and so tissue/organ damage continues that may account for persistence of inflammation even when the patients are on antiinflammatory and immunosuppressive medicines. In view of this, it is imperative that the institution of proresolution-inducing agents needs to be employed to obtain full remission and restore normal physiological function of the target tissues/organs in MS. Such endogenous proresolution-inducing molecules include lipoxins, resolvins, protectins, maresins, NO (NO can be both pro- and antiinflammatory in nature depending on the amount of NO produced: excess NO is proinflammatory, whereas physiological amounts are antiinflammatory), nitrolipids, 15 deoxyD12-14PGJ2, PGD2, antiinflammatory cytokines such as IL-4, IL-10, and some polyunsaturated fatty acids (PUFAs). Based on this hypothesis, it is suggested that progression and flares of MS are due to increased production of proinflammatory molecules IL-6, TNF-a, macrophage MIF, high mobility group box 1 (HMGB1), free radicals, and lipid mediators such as prostaglandins (PGs), leukotrienes (LTs), and/or decreased formation and release of antiinflammatory molecules: IL-4, IL-10, transforming growth factor-b, and lipoxins, resolvins, protectins, maresins, and nitrolipids.
desaturases. EPA forms the precursor of the three series of prostaglandins and the five series of LTs. EPA can be elongated to form docosahexaenoic acid (DHA, 22:6, u-3). AA, EPA, and DHA also form precursors to a group of novel compounds: lipoxins, resolvins, protectins, and maresins [2–7] that have antiinflammatory action (Fig. 1 shows the metabolism of essential fatty acids). Eicosanoids bind to G-protein-coupled receptors on many cell types, mediate virtually every step of inflammation, and are found in inflammatory exudates; their synthesis is increased at sites of inflammation. Non-steroidal antiinflammatory drugs such as aspirin inhibit cyclooxygenase (COX) activity and thus are believed to bring about their antiinflammatory action. Lipoxins, resolvins, protectins, and maresins There are two COX enzymes, the constitutively expressed COX-1 and the inducible enzyme COX-2. Different types of PGs are formed by the action of COX enzymes depending on the substrate fatty acid from which they are derived. Different types of PGs have different actions and sometimes diametrically opposite actions. There are three types of lipoxygenases that are present in only a few types of cells. 5-Lipoxygenase (5-LO), present in neutrophils, produces 5-hydroxyeicosatetraenoic acid (5-HETE), which is chemotactic for neutrophils and is converted into LTs. LTB4, a potent chemotactic and activator of neutrophils, induces aggregation and adhesion of leukocytes to vascular endothelium, generation of reactive oxygen species, and release of lysosomal enzymes. The cysteinyl-containing leukotrienes C4, D4, and E4 (LTC4, LTD4, and LTE4) induce vasoconstriction, bronchospasm, and vascular permeability in venules. LTs mediate their actions
Metabolism of essential fatty acids with specific reference to inflammation cis-Linoleic acid (LA, 18:2 u-6) and a-linolenic acid (ALA, 18:3 u-3) are essential nutrients because they cannot be synthesized by the human body and hence are called “essential fatty acids.” LA is converted to gamma-linolenic acid (GLA, 18:3, u-6) by the action of the enzyme D6 desaturase, and GLA is elongated to form di-homo-GLA (20:3, u-6), the precursor of the one series of prostaglandins. D6 desaturase is the rate-limiting step in the metabolism of essential fatty acids. Di-homo-GLA can also be converted to arachidonic acid (AA, 20:4, u-6) by the action of the enzyme D5 desaturase. AA forms the precursor of two series of prostaglandins, thromboxanes, and the four series LTs. ALA is converted to eicosapentaenoic acid (EPA, 20:5, u-3) by D6 and D5
Fig. 1. Metabolism of essential fatty acids.
U. N. Das / Nutrition 28 (2012) 951–958
by binding to cysteinyl leukotreine 1 (CysLT1) and CysLT2 receptors. Lipoxins (LXs) are generated from AA, resolvins from EPA and DHA, and protectins from by transcellular biosynthetic mechanisms involving two cell populations. Neutrophils produce intermediates in LX synthesis, and these are converted to LXs by platelets interacting with leukocytes. LXA4 and LXB4 are generated by the action of platelet 12-lipoxygenase on neutrophilderived LTA4. LXs have antiinflammatory actions [8] and are negative regulators of LT synthesis and thus resolve inflammation. An inverse relationship generally exists between LXs and LTs and the balance between these two molecules appears to be crucial in the determination of degree of inflammation and its final resolution [2–7]. Aspirin-triggered 15 epimer LXs (ATLs), resolvins, and protectins The formation of ATLs is a potent counterregulator of polymorphonuclear neutrophils (PMNs)-mediated injury and acute inflammation. Acetylated COX-2 enzyme of endothelial cells generates 15R-hydroxyeicosatetraenoic acid (15R-HETE) from AA that is converted by activated PMNs to the 15-epimeric LXs that have potent antiinflammatory properties [3–7]. This cross-talk between endothelial cells and PMNs, leading to the formation of 15R-HETE and its subsequent conversion to 15-epimeric LXs by aspirin-acetylated COX-2, is a protective mechanism to prevent local inflammation by regulating the motility of PMNs, eosinophils, and monocytes [6,7]. Endothelial cells also oxidize AA, EPA, and DHA via the P450 enzyme system to form various hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids such as 11,12-epoxyeicosatetraenoic acid(s) that possess antiinflammatory actions [7–12]. Akin to the formation of 15R-HETE and 15-epimeric LXs from AA, similar compounds are also formed from EPA and DHA. In the presence of aspirin, activated COX-2 of human endothelial cells converts EPA to 18R-HEPE, 18-HEPE, and 15R-HEPE. Activated human PMNs, in turn, converted 18R-HEPE to 5,12,18R-triHEPE and 15R-HEPE to 15-epi-LXA5 by their 5-lipoxygenase. Both 18RHEPE and 5,12,18R-triHEPE inhibited LTB4-stimulated PMN transendothelial migration. 5,12,18R-triHEPE effectively competed with LTB4 for its receptors and inhibited PMN infiltration and suppressed LT-mediated inflammation [4,5,7,13]. The conversion of EPA by human endothelial cells with upregulated COX-2 treated with ASA of EPA to 15-epi-LX also termed aspirin-triggered LX (ATL) and to 18R-HEPE and 15RHEPE is interesting. These compounds, in turn, are used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15RLX(5) and 5,12,18R-triHEPE, which are potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analog > 5,12,18R-triHEPE > 18R-HEPE). The formation of these bioactive lipid mediators via COX-2-nonsteroidal antiinflammatory drug-dependent oxygenations and cell-cell interactions inhibits inflammation [7,13]. COX-2 in the presence of aspirin can transform enzymatically DHA to 17R series of hydroxy DHAs that, in turn, are converted enzymatically by PMNs to di- and trihydroxy-containing docosanoids [7,13,14]. The conversion of DHA by leukocytes, brain, and glial cells to 17S-hydroxy-containing docosanoids denoted as docosatrienes (the main bioactive member of the series was 10,17S-docosatriene) and 17S series resolvins reduces leukocyte infiltration in vivo and blocks cytokine production by glial cells that may explain the antiinflammatory actions of DHA.
953
Similar small molecular weight compounds are also generated from AA, EPA, and DHA: 15R-hydroxy-containing compounds from AA, 18R series from EPA, and 17R-hydroxy series from DHA that have antiinflammatory actions, resolve inflammation, and hence are called “resolvins.” Resolvins inhibited cytokine generation, leukocyte recruitment, leukocyte diapedesis, and exudate formation. The formation of resolvins from acetylated COX-2 are generated via transcellular biosynthesis (e.g., due to cell-cell communication between endothelial cells and PMNs), and their main purpose is to suppress inflammation. Resolvins inhibited brain ischemia-reperfusion injury [14]. It is possible that lipoxins, resolvins, and protectins (docosanoids are also called as protectins because they have neuroprotective actions) behave as endogenous antiinflammatory and cytoprotective molecules. The general cytoprotective properties that have been attributed to AA, EPA, and DHA can be related to their conversion to lipoxins, resolvins, and docosanoids (protectins) (Figs. 2-4 show the formation of lipoxins, resolvins, and protectins from their precursors). Hence, any defect in the synthesis of lipoxins, resolvins, and protectins or their inappropriate degradation could lead to perpetuation of inflammation as seen in MS and other inflammatory conditions.
Anti-inflammatory molecule lipoxin A4 is detectable in urine LX4, generated by LO transformation of AA, possess potent anti-inflammatory activity in vivo and temporal biosynthesis of LX, concurrent with spontaneous resolution, has been observed during exudate formation [9–11]. LXs, resolvins, protectins, and maresins are detectable in the plasma. However, if any compound that one wishes to use as a biomarker of a disease process can be detected in the urine, then it will be feasible to bring such a marker to the clinic rather rapidly. Recently, a new extraction technique, more selective for LX, which abolishes background contamination and minimizes the unspecific reading, was developed. This new method showed that urine from healthy subjects contains LXA4 [15]. Subsequently, it was shown [16] that exercise, which is antiinflammatory in nature [17], significantly increased urinary excretion in healthy volunteers (0.061 0.023 versus 0.113 0.057 ng/mg creatinine; P ¼ 0.028). These findings confirm that alterations in the urinary excretion of LXA4 can be used as a reflection of changes in its (LXA4) formation to monitor changes in the inflammatory lesions
Fig. 2. Scheme showing the formation of lipoxin A4 from arachidonic acid.
954
U. N. Das / Nutrition 28 (2012) 951–958
Fig. 3. Scheme showing the formation of various lipoxins from arachidonic acid as a result of intercellular communication, coordination, and cooperation.
and antiinflammatory nature of exercise could be attributed, in part, to enhanced formation of LXA4. In a further extension of this work, it was reported that urinary levels of LXA4 were decreased, whereas that of cysteinyl leukotrienes increased in volunteers aged 26 to over 100 y, leading to a profound unbalance of the LXA(4)/cysteinyl leukotrienes ratio that may be considered an index of the endogenous antiinflammatory potential [18]. These results suggest that endogenous antiinflammatory mechanisms become less efficient with age that could result in increased susceptibility to inflammatory disorders with advancing age. A recent study revealed that in HSP nephritis, concordant with the gradually increased severity of the disease, the expressions of 15-lipoxygenase and the levels of urinary LXA4 gradually decreased and the expressions of LTC4 synthase and the urinary
LTE4 and LTB4 gradually increased [19]. These data suggest that LTs play a proinflammatory role and insufficiency of LXA4 may be responsible for the severity of the illness. Absence or decreased levels of LXA4 that act as a “stop signal” of inflammatory process may be responsible for the continued inflammation. Based on these findings, measurement of plasma and urinary LXs and LTs and possibly other eicosanoids could be used as a marker of inflammatory process in various organs in the body. Because there is a good correlation between plasma (blood) and urinary levels of LXs and LTs and the degree of inflammatory process, measurement of plasma and urinary levels of various eicosanoids may serve as a marker of inflammation and changes in their respective levels could predict the progression, resolution, and continuation of the inflammatory process and diseases in which inflammation plays a significant role such as MS.
Fig. 4. Scheme showing the formation of resolvin E1 from EPA.
U. N. Das / Nutrition 28 (2012) 951–958
Anti-inflammatory cytokines IL-4 and IL-10 enhance LXA4 synthesis In this context, it is noteworthy that antiinflammatory cytokines IL-4 and IL-10 trigger the conversion of AA, EPA, and DHA to lipoxins, resolvins, protectins, and maresins, suggesting a mechanism by which they are able to suppress inflammation [20]. For example, IL-4 up-regulated [it may be noted here that 15-S-HETE (a 15-LO product) and lipoxins (interaction products between 5-LO and either 12-LO or 15-LO) counteract the proinflammatory actions of LTs] 15-LO gene expression in human leukocytes. Glomerular 12/15-LO mRNA increased significantly over controls 24 and 48 h after nephrotoxic serum injection and then decreased at 72 h. RNA from nephrotoxic-serum-injected glomeruli contained higher levels of 12/15-LO mRNA than that from unstimulated peripheral leukocytes, suggesting that 12/15LO transcription is up-regulated locally in native and/or infiltrating glomerular cells. Glomerular IL-4 mRNA increased markedly 16 h postnephrotoxic serum injection and was then reduced, suggesting a potential role for T-cell-derived IL-4 in directing the expression of 12/15-LO during glomerulonephritis. This suggested tandem-regulated in vivo gene expression for IL-4 and LO, both of which promote counterinflammatory influences in immune-complex-mediated injury and it is reasonable to predict that such events may also occur in MS. Balance between LXA4 and LTs determines the degree of inflammation The 5-lipoxygenated metabolites of AA, the LTs, are major mediators of early glomerular hemodynamic and structural deterioration during experimental glomerulonephritis that are generated largely by infiltrating leukocytes but can also occur by intrinsic glomerular cells via transcellular metabolism of intermediates. In animal models of glomerulonephritis and other renal pathologic states, LTs have been shown to exert adverse effects in the glomerulus. LTB4 augments neutrophil infiltration, and LTC4 and LTD4 mediate potent vasoconstrictor effects on the glomerular microcirculation. Selective blockade of the 5lipoxygenase pathway produced a significant amelioration of the deterioration of renal hemodynamic and structural parameters. On the other hand, 15-S-HETE, the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of AA, are also generated in the course of glomerular injury that antagonizes LT-induced neutrophil chemotaxis, and lipoxin A4 antagonized the effects of LTD4 and LTC4 on the glomerular microcirculation. Thus, the contrasting effects of 5- and 15lipoxygenase products represent endogenous pro- and antiinflammatory influences that ultimately determine and regulate the extent and severity of glomerular inflammation [21–24]. These results are in favor of the proposal that antiinflammatory cytokines IL-4 and IL-10 induce the expression and synthesis of antiinflammatory lipid mediators lipoxins, resolvins, protectins, and maresins in addition to their ability to suppress the production of proinflammatory cytokines such as IL-2, IL-6, TNF-a, MIF, HMGB1, and LTs. PUFAs and lipoxins bind to G-protein-coupled receptors to suppress inflammation It is noteworthy that monocytes and macrophages express an extensive repertoire of G-protein-coupled receptors (GPCRs) that regulate inflammation and immunity. A number of GPCRs
955
(e.g., Edg5, P2ry2, and 6) have been reported to be expressed by macrophages and two cell types closely related to macrophages (osteoclasts and dendritic cells), whereas Gpr84 expression was largely restricted to macrophage populations and granulocytes [25]. It is now apparent that many PUFAs, especially AA, EPA, and DHA, and their metabolites such as eicosanoids, lipoxins, resolvins, protectins, and maresins, also function directly as agonists at a number of GPCRs. Tissue distribution studies and siRNA knockdown experiments have indicated key roles for these GPCRs in glucose homeostasis, adipogenesis, leukocyte recruitment, and inflammation [26]. A recent study showed that the G-protein-coupled receptor 120 (GPR120) functions as a u-3 fatty acid receptor/sensor. Stimulation of GPR120 with u3 fatty acids (EPA and DHA) induced broad antiinflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects were abrogated by GPR120 knockdown. The u-3 fatty acid treatment not only inhibited inflammation but also enhanced systemic insulin sensitivity in wild-type mice, but was without effect in GPR120 knockout mice. These results suggest that GPR120 is a functional u-3 fatty acid receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation [27]. Thus, it is likely that PUFAs and their antiinflammatory products such as lipoxins, resolvins, protectins, and maresins inhibit the production of various proinflammatory molecules including MIF and HMGB1 and thus suppress inflammation in diseases such as MS (Fig. 5). The human brain is rich in AA, EPA, and DHA (DHA > AA > EPA), which constitute as much as 30% to 50% of the total fatty acids in the brain, where they are predominantly associated with membrane phospholipids. Nerve growth cones are highly enriched with AA-releasing phospholipases, which have been implicated in neurite outgrowth. Cell membrane expansion occurs through the fusion of transport organelles with plasma membrane, and syntaxin 3, a plasma membrane protein that is important in the growth of neurites, is a direct target for AA, DHA, and other PUFAs. It has been shown that AA, DHA, and other PUFAs but not saturated and monounsaturated fatty acids activate syntaxin 3. Syntaxin1 that is specifically involved in fast calcium-triggered exocytosis of neurotransmitters is sensitive to AA, suggesting that AA is involved in both exocytosis of neurotransmitters and neurite outgrowth. SNAP25 (synaptosomal-associated protein of 25 kDa), a syntaxin partner implicated in neurite outgrowth, interacts with syntaxin 3 only in the presence of AA that allowed the formation of the binary syntaxin 3-SNAP25 complex. AA stimulated syntaxin 3 to form the ternary SNARE complex (soluble N-ethylmaleimide-sensitive factor attachment protein receptor), which is needed for the fusion of plasmalemmal precursor vesicles into the cell surface membrane that leads to membrane fusion. The intrinsic tyrosine fluorescence of syntaxin 3 showed marked changes on the addition of AA, DHA, LA, and ALA, whereas saturated and monounsaturated (oleic acid) fatty acids were ineffective. Thus, AA and DHA change the a-helical syntaxin structure to expose the SNARE motif for immediate SNAP25 engagement that facilitates neurite outgrowth [28,29]. In addition, PUFAs have the ability to modulate the actions of various neurotransmitters and hypothalamic peptides (see ref. [30]). One major action of AA, EPA, and DHA in the brain could be not only to form precursors to antiinflammatory lipoxins, resolvins, protectins, and maresins but also to enhance synaptic formation and neurite outgrowth and to facilitate neurotransmission that are impaired in MS.
956
U. N. Das / Nutrition 28 (2012) 951–958
Fig. 5. Scheme showing the role of prostaglandins and leukotrienes and lipoxins in MS and its resolution. () Inhibition or suppression of action; (þ) activation or enhancement of action. There are three classes of phospholipases that control the release of AA and other PUFAs: calcium-independent PLA2 (iPLA2), secretory PLA2 (sPLA2), and cytosolic PLA2 (cPLA2) [38]. Each class of PLA2 is further divided into isoenzymes for which there are 10 for mammalian sPLA2, at least 3 for cPLA2, and 2 for iPLA2. During the early phase of inflammation, COX-derived PGs and lipoxygenase-derived LTs initiate exudate formation and inflammatory cell influx [9,39]. TNF-a causes an immediate influx of neutrophils concomitant with PGE2 and LTB4 production, whereas during the phase of resolution of inflammation an increase in LXA4 (lipoxin A4), PGD2, and its product 15deoxyD12-14PGJ2 formation occurs that induces the resolution of inflammation with a simultaneous decrease in PGE2 synthesis that stops neutrophil influx and enhances phagocytosis of debris [40,41]. Thus, there are two waves of release of AA and other PUFAs: one at the onset of inflammation that causes the synthesis and release of PGE2 and a second at resolution for the synthesis of antiinflammatory PGD2, 15deoxyD12-14PGJ2, and lipoxins that are necessary for the suppression of inflammation. Thus, COX-2 enzyme has both harmful and useful actions by virtue of its ability to give rise to proinflammatory and antiinflammatory PGs and LXs. Increased type VI iPLA2 protein expression was the principal isoform expressed from the onset of inflammation up to 24 h, whereas type IIa and V sPLA2 were expressed from the beginning of 48 h until 72 h, whereas type IV cPLA2 was not detectable during the early phase of acute inflammation but increased progressively during resolution, peaking at 72 h. This increase in type IV cPLA2 was mirrored by a parallel increase in COX-2 expression [42]. The increase in cPLA2 and COX-2 occurred in parallel, suggesting a close enzymatic coupling between these two. Thus, there is a clear-cut role for different types of PLA2 in distinct and different phases of inflammation. Selective inhibition of cPLA2 resulted in the reduction of pro-inflammatory molecules PGE2, LTB4, IL-1b, and platelet-activating factor (PAF). Furthermore, inhibition of types IIa and V sPLA2 not only decreased PAF and LXA4 (lipoxin A4) but also resulted in a reduction in cPLA2 and COX-2 activities. These results suggest that sPLA2-derived PAF and LXA4 induce COX-2 and type IV cPLA2. IL-1b induced cPLA2 expression, suggesting that IL-1 not only induces inflammation but also enhances cPLA2 expression to initiate the resolution of inflammation [43,44]. Synthetic glucocorticoid dexamethasone inhibited both cPLA2 and sPLA2 expression, whereas type IV iPLA2 expression is refractory to its suppressive actions [42,45,46]. Activated iPLA2 contributes to the conversion of inactive proIL-1b to active IL-1b that, in turn, induces cPLA2 expression, which is necessary for resolution of inflammation. LXs, especially LXA4, inhibit TNF-a-induced production of ILs, promote TNF-a mRNA decay, TNF-a secretion, and leukocyte trafficking, and thus attenuated inflammation. In a recent study [47], it was observed that in a mouse model of spinal cord injury (SCI) two cytosolic forms [calcium-dependent PLA2 group IVA (cPLA2 GIVA) and calcium-independent PLA2 group VIA (iPLA2 GVIA)], and a secreted form [secreted PLA2 group IIA (sPLA2 GIIA)] are up-regulated and these PLA2s play differing roles. cPLA2 GIVA mediated protection, whereas sPLA2 GIIA and, to a lesser extent, iPLA2 GVIA were found to be detrimental. Furthermore, completely blocking all three PLA2s worsened the outcome, whereas partial inhibition of all the three PLA2s showed the most beneficial action. It was noted that enhanced expression of cPLA2 mediated its beneficial effects via the prostaglandin EP1 receptor. These results suggest that drugs that inhibit detrimental forms of PLA2 (sPLA2 and iPLA2) and up-regulation of the protective form (cPLA2) is likely to be useful in the treatment of SCI. For further details, see text.
Hypothesis: A deficiency of LXA4 and excess of LTs and PGE2 may be responsible for MS Based on the evidence presented above and the role of LXA4 and LTs and PGE2 in inflammation, it is quite logical to suggest that a deficiency of LXA4 and other PGs that have
antiinflammatory actions and/or an excess of LTs and PGE2 initiate and perpetuate inflammation in MS. Because it is possible to estimate these compounds in the plasma, urine, and possibly the cerebrospinal fluid (CSF), I propose that progression and flares of MS are due to decreased production of LXA4 and enhanced production of LTs by the neurons and/or infiltrating
U. N. Das / Nutrition 28 (2012) 951–958
leukocytes and macrophages. These molecules can be detected and estimated in the plasma, urine, and possibly the CSF [15,16, 18]. Furthermore, the plasma, urinary, and CSF levels of LXA4 and LTs may also be used to predict prognosis and response to treatment. If the plasma, urinary, and CSF LXA4 levels revert to normal or are slowly increasing with and without decrease in the plasma, urinary, and CSF levels of LTs, it can be considered an indication that the patient is responding to treatment and MS is ameliorating. The urinary levels of LXA4 and LTs can be compared to their plasma and CSF concentrations and to the clinical picture and Expanded Disability Status Scale, Multiple Sclerosis Functional Composite (or the Scripps Rating Scale), Cognitive Function Tests, and various imaging technologies such as computed tomography and magnetic resonance imaging scans of the brain to know the progress of MS. Because resolvins, protectins, and maresins are also antiinflammatory lipid molecules derived from EPA and DHA and have a role in the resolution of inflammation, it is predicted that they may also have the same significance as that of lipoxins in MS. Hence, it is worthwhile to measure the plasma, urinary, and CSF levels of resolvins, protectins, and maresins in addition to lipoxins in the plasma, urine, and CSF of patients with MS to predict prognosis and response to treatment. A decrease in their levels in the plasma, urine, and CSF indicates continued inflammation and damage to various neurological structures in the brain, whereas enhancement in their levels indicates resolution of inflammation and amelioration of MS.
957
decreased formation of lipoxins, resolvins, protectins, and maresins may have exacerbated EAE/MS. These results indicate that lipids play a significant role in MS [33]. Lipoxins, resolvins, protectins, and maresins are not only antiinflammatory in nature but also enhance wound healing, resolve inflammation, and have cytoprotective and neuroprotective actions [2–7]. Hence, when the local concentrations of lipoxins, resolvins, protectins, and maresins are low, which could be secondary to reduced levels of PUFAs, it would lead to continued inflammation and neuronal damage, whereas when their (PUFAs, lipoxins, resolvins, protectins, and maresins) levels are enhanced, inappropriate inflammation will be suppressed, leading to healing and neuronal protection. In addition, lipoxins, resolvins, protectins, and maresins enhance stem cell survival, proliferation, and neuronal differentiation [34–37] that could aid in the healing of the neuronal damage that occurs in MS and augment the recovery process. This implies that methods designed to enhance the levels of PUFAs, and their anti-inflammatory products lipoxins, resolvins, protectins, and maresins, or administration of synthetic analogs of lipoxins, resolvins, protectins, and maresins may be of significant benefit in the prevention and management of MS. Acknowledgment Dr. U. N. Das is in receipt of the Ramalingaswami fellowship of the Department of Biotechnology, India for the tenure of this study.
Involvement of eicosanoids and lipoxins, resolvins, protectins, and maresins in MS
References
Studies of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have shown that autoreactive T cells secreting IL-17 (TH17 cells) and IFN-g (TH1 cells) are involved in EAE/MS pathogenesis. Using an AA-cascade-targeted lipidomics approach, it was reported that microsomal PGE synthase 1 (mPGES-1) plays a key role in the inflammation seen in EAE. PGD2 was produced constitutively in the spinal cord of naive mice, whereas induction of EAE lesions in the production of PGE2 was favored and PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. PGD2, PGI2, and 5-LO metabolites such as lipoxins, resolvins, and protectins have antiinflammatory action (Fig. 5). Furthermore, mPGE-1/ mice showed less severe symptoms of EAE and lower production of IL-27 and IFN-g than mPGEs-1þ/þ mice. Immunohistochemistry on the central nervous system of EAE mice and MS patients revealed overt expression of mPGES-1 protein in microglia/macrophages [31]. It was noted that of all the eicosanoids examined, only PGE2 was significantly elevated in the spinal cords of EAE mice. PGE2 produced by microglia/ macrophages in inflammatory foci may aggravate EAE by promoting the differentiation of TH1 and the expression of TH17 cells through EPs (eicosanoid receptors). Furthermore, it was noted that in PGI2 that enhances endothelial barrier function and thus protects mice from EAE, production is decreased, whereas that of PGD2, an antiinflammatory molecule, was reduced [31]. A significant suppression of 5-LO metabolites was noted and 5-LO/ mice developed more severe EAE than control wild-type mice [32], suggesting that both increased formation of PGE2 and decreased formation of 5-LO products such as lipoxins, resolvins, protectins, and maresins play a significant role in EAE and MS. Unfortunately, in this study [31], lipoxins, resolvins, protectins, and maresins were not measured. It was reported that 12/15-LO deficiency conferred more severe EAE pathology [32], suggesting that
[1] Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 2009;65:239–48. [2] Das UN. Clinical laboratory tools to diagnose inflammation. Adv Clin Chem 2006;41:189–229. [3] Claria J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci USA 1995;92:9475–9. [4] Das UN. Essential fatty acids: Biochemistry, physiology, and pathology. Biotechnol J 2006;1:420–39. [5] Das UN. Essential fatty acidsda review. Curr Pharmaceutical Biotechnol 2006;7:467–82. [6] Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation signals in resolution. Nat Immunol 2001;2:612–9. [7] Das UN. Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation. J Inflammation Res 2010;3:143–70. [8] Zordoky BN, El-Kadi AO. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol Ther 2010;125:446–63. [9] Nithipatikom K, Gross GJ. Review article: epoxyeicosatrienoic acids: novel mediators of cardioprotection. J Cardiovasc Pharmacol Ther 2010;15:112–9. [10] Campbell WB, Fleming I. Epoxyeicosatrienoic acids and endotheliumdependent responses. Pflugers Arch 2010;459:881–95. [11] Arnold C, Konkel A, Fischer R, Schunck WH. Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol Rep 2010;62:536–47. [12] Gao L, Yin H, Milne GL, Porter NA, Morrow JD. Formation of F-ring isoprostane-like compounds (F3-isoprostanes) in vivo from eicosapentaenoic acid. J Biol Chem 2006;281:14092–9. [13] Serhan CN, Clish CB, Brannon J, Colgan SP, Gronert K, Chiang N. Antimicroinflammatory lipid signals generated from dietary N-3 fatty acids via cyclooxygenase-2 and transcellular processing: a novel mechanism for NSAID and N-3 PUFA therapeutic actions. J Physiol Pharmacol 2000;51(4 Pt 1):643–54. [14] Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem 2003;278:14677–87. [15] Romano M, Luciotti G, Gangemi S, Marinucci F, Prontera C, D’Urbano E, et al. Urinary excretion of lipoxin A(4) and related compounds: development of new extraction techniques for lipoxins. Lab Invest 2002;82:1253–4.
958
U. N. Das / Nutrition 28 (2012) 951–958
[16] Gangemi S, Luciotti G, D’Urbano E, Mallamace A, Santoro D, Bellinghieri G, et al. Physical exercise increases urinary excretion of lipoxin A4 and related compounds. J Appl Physiol 2003;94:2237–40. [17] Das UN. Anti-inflammatory nature of exercise. Nutrition 2004;20:323–6. [18] Gangemi S, Pescara L, D’Urbano E, Basile G, Nicita-Mauro V, Davı G, et al. Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels. Exp Gerontol 2005;40:612–4. [19] Wu SH, Liao PY, Yin PL, Zhang YM, Dong L. Inverse temporal changes of lipoxin A4 and leukotrienes in children with Henoch-Schönlein purpura. Prostaglandins Leukot Essent Fatty Acids 2009;80:177–83. [20] Katoh T, Lakkis FG, Makita N, Badr KF. Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Kidney Int 1994;46:341–9. [21] Nassar GM, Badr KF. Role of leukotrienes and lipoxygenases in glomerular injury. Miner Electrolyte Metab 1995;21:262–70. [22] Papayianni A, Serhan CN, Phillips ML, Rennke HG, Brady HR. Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis. Kidney Int 1995;47:1295–302. [23] O’Meara YM, Brady HR. Lipoxins, leukocyte recruitment and the resolution phase of acute glomerulonephritis. Kidney Int Suppl 1997;58:S56–61. [24] Wu SH, Liao PY, Yin PL, Zhang YM, Dong L. Elevated expressions of 15lipoxygenase and lipoxin A4 in children with acute poststreptococcal glomerulonephritis. Am J Pathol 2009;174:115–22. [25] Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, et al. Expression analysis of G protein-coupled receptors in mouse macrophages. Immunome Res 2008;4:5. [26] Milligan G, Stoddart LA, Brown AJ. G protein-coupled receptors for free fatty acids. Cell Signal 2006;18:1360–5. [27] Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010;142:687–98. [28] Darios F, Davletov B. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 2006;440:813–7. [29] Calderon F, Kim H-Y. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem 2004;90:979–88. [30] Das UN. Metabolic syndrome pathophysiology: Role of essential fatty acids. Ames, IA: Wiley-Blackwell; 2010. [31] Kihara Y, Matsushita T, Kita Y, Uematsu S, Akira S, Kira J, et al. Targeted lipidomic reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad Sci USA 2009;106:21807–12. [32] Emerson MR, LeVine SM. Experimental allergic encephalomyelitis is exacerbated in mic2 deficient for 12/15-lipoxygenase or 5-lipoxygenase. Brain Res 2004;1021:140–5.
[33] Kanter JL, Narayana S, Ho PP, Catz I, Warren KG, Sobel RA, et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 2006;12:138–43. nchez-Ruiz A, Benton HP, Trauger SA, [34] Yanes O, Clark J, Wong DM, Patti GJ, Sa et al. Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol 2010;6:411–7. [35] Bazan NG. The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling. Cell Mol Neurobiol 2006;26:901–13. [36] Das UN. Influence of polyunsaturated fatty acids and their metabolites on stem cell biology. Nutrition 2011;27:21–5. [37] Das UN. Molecular Basis of Health and Disease. New York: Springer; 2011. [38] Bonventre JV. Phospholipase A2 and signal transduction. J Am Soc Nephrol 1992;3:128–50. [39] Das UN. Radiation resistance, invasiveness and metastasis are inflammatory events that could be suppressed by lipoxin A(4). Prostaglandins, leukotrienes, and essential fatty acids 2012;86:3–11. [40] Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol 2000;164:1663–7. [41] Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 1999;5:698–701. [42] Gilroy DW, Newson J, Sawmynaden P, Willoughby DA, Croxtall JD. A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation. FASEB J 2004;18:489–98. [43] Cominelli F, Nast CC, Llerena R, Dinarello CA, Zipser RD. Interleukin 1 suppresses inflammation in rabbit colitis. Mediation by endogenous prostaglandins. J Clin Invest 1990;85:582–6. [44] Schwab JH, Anderle SK, Brown RR, Dalldorf FG, Thompson RC. Pro- and anti-inflammatory roles of interleukin-1 in recurrence of bacterial cell wall-induced arthritis in rats. Infect Immun 1991;59:4436–42. [45] Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, et al. Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002;196:1025–37. [46] Croxtall JD, Choudhury Q, Tokumoto H, Flower RJ. Lipocortin-1 and the control of arachidonic acid release in cell signalling. Glucocorticoids inhibit G protein-dependent activation of cPLA2 activity. Biochem Pharmacol 1995;50:465–74. [47] Lo’pez-Vales R, Ghasemlou N, Redensek A, Kerr BJ, Barbayianni E, Antonopoulou G, et al. Phospholipase A2 superfamily members play divergent roles after spinal cord injury. FASEB J 2011;25:4240–52.
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Review
Is multiple sclerosis a proresolution deficiency disorder? Undurti N. Das MD, FAMS * UND Life Sciences, Shaker Heights, Ohio, USA School of Biotechnology, Jawaharlal Nehru Technological University, Kakinada, India Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering, Visakhapatnam, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 September 2011 Accepted 26 December 2011
The inflammatory process seen in multiple sclerosis is due to an excess production of proinflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-a, interferons, macrophage migration inhibitory factor, HMGB1 (high mobility group B1), and, possibly, a reduction in antiinflammatory cytokines IL-10, IL-4, and transforming growth factor-b that leads to increased secretion of reactive oxygen species, including nitric oxide, resulting in neuronal damage. It is suggested that failure of production of adequate amounts of resolution-inducing molecules lipoxins, resolvins, and protectins that suppress inflammation and reactive oxygen species production, enhance wound healing, and have neuroprotective properties results in inappropriate inflammation and delay in the healing/repair process, and so neuronal damage continues, as seen in multiple sclerosis. Hence, methods designed to enhance the production and/or administration of lipoxins, resolvins, and protectins may form a new approach in the prevention and treatment of multiple sclerosis and other similar autoimmune diseases. Ó 2012 Elsevier Inc. All rights reserved.
Keywords: Multiple sclerosis Inflammation Lipoxins Resolvins Protectins Free radicals Reactive oxygen species Cytokines T cells Macrophages Nitric oxide
Introduction Multiple sclerosis (MS) is an inflammatory disease of uncertain origin that leads to destruction of myelin sheaths around axons in the brain and spinal cord. Disease onset usually occurs in young adults and is more common in females. MS may not reduce lifespan but certainly erodes the quality of life of both sufferers and their families. MS presents in a variety of subtypes: i. ii. iii. iv.
Relapsing-remitting Secondary-progressive Primary-progressive Progressive-relapsing
There is no cure for MS [1]. Several antiinflammatory drugs are available to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability in relapsing MS, but none of these treatments directly act on the underlying neurodegenerative process in MS. Although genetic, environmental, and sex hormonal factors have been implicated in the * Corresponding author. Tel.: þ1 216-231-5548; fax: þ1 928-833-0316. E-mail address: [email protected] 0899-9007/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2011.12.016
pathogenesis of MS, it is known that several cytokines, nitric oxide (NO), free radicals, a deranged immune system, a deficient anti-oxidant defenses, and Toll-like receptors have a significant role in both the initiation and the perpetuation of the inflammatory process observed. It is thought that an unknown non-self-antigen mimics proteins in myelin. This antigen is presented on the surface of macrophages in combination with class 2 MHC. The resulting stimulation of Th1 T-helper lymphocytes causes their expression of lymphocyte function-associated antigen-1 and very late activation antigen-4. These T-helper cells may now bind to the cognate adhesion molecules, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, on vascular endothelial cells. The release of proteases permits the T-helper cells to cross the endothelium and enter the central nervous system. The destruction of myelin proceeds in the three following ways: Tumor necrosis factor-a (TNF-a) from Th1 lymphocytes TNF-a, oxygen free radicals, nitric oxide, and proteases from activated macrophages Antibody-mediated complement activation MS classically has been considered to be primarily a demyelinating disease in which neuronal death occurs from the early
952
U. N. Das / Nutrition 28 (2012) 951–958
stages of the disease. It is probably this process of neuronal loss that contributes to the accumulating disability in MS. The susceptibility to develop MS in a given individual seems to have at least partly a genetic basis, although this is still not very clear. Once the inflammatory process is triggered, this leads to the production of a variety of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, TNF-a, interferons (IFNs), macrophage migration inhibitory factor (MIF), high mobility group B1 (HMGB1), and possibly a reduction in the elaboration of antiinflammatory cytokines such as IL-10, IL-4, and transforming growth factor-b. This imbalance between the pro- and antiinflammatory cytokines coupled with increased secretion of free radicals such as superoxide anion (O2.), hydrogen peroxide (H2O2), singlet oxygen, inducible NO, and other reactive oxygen species by activated monocytes, macrophages, polymorphonuclear leukocytes, T cells, Kupffer cells, glial cells in the brain, and other organ-specific reticuloendothelial cells would ultimately cause target tissue/organ damage seen in MS. I propose that continued inflammatory events seen in MS could be due to failure of the resolution of inflammation. Thus, the balance between inflammation and resolution is disturbed more in favor of proinflammatory events and/or failure of resolution-inducing molecules to be produced at the most appropriate time, leading to non-resolution of inflammation. In other words, even after the inciting agent responsible for the initiation of inflammation is removed, inappropriate inflammation continues simply because resolution failed to occur. This leads to a delay in the healing/repair process and so tissue/organ damage continues that may account for persistence of inflammation even when the patients are on antiinflammatory and immunosuppressive medicines. In view of this, it is imperative that the institution of proresolution-inducing agents needs to be employed to obtain full remission and restore normal physiological function of the target tissues/organs in MS. Such endogenous proresolution-inducing molecules include lipoxins, resolvins, protectins, maresins, NO (NO can be both pro- and antiinflammatory in nature depending on the amount of NO produced: excess NO is proinflammatory, whereas physiological amounts are antiinflammatory), nitrolipids, 15 deoxyD12-14PGJ2, PGD2, antiinflammatory cytokines such as IL-4, IL-10, and some polyunsaturated fatty acids (PUFAs). Based on this hypothesis, it is suggested that progression and flares of MS are due to increased production of proinflammatory molecules IL-6, TNF-a, macrophage MIF, high mobility group box 1 (HMGB1), free radicals, and lipid mediators such as prostaglandins (PGs), leukotrienes (LTs), and/or decreased formation and release of antiinflammatory molecules: IL-4, IL-10, transforming growth factor-b, and lipoxins, resolvins, protectins, maresins, and nitrolipids.
desaturases. EPA forms the precursor of the three series of prostaglandins and the five series of LTs. EPA can be elongated to form docosahexaenoic acid (DHA, 22:6, u-3). AA, EPA, and DHA also form precursors to a group of novel compounds: lipoxins, resolvins, protectins, and maresins [2–7] that have antiinflammatory action (Fig. 1 shows the metabolism of essential fatty acids). Eicosanoids bind to G-protein-coupled receptors on many cell types, mediate virtually every step of inflammation, and are found in inflammatory exudates; their synthesis is increased at sites of inflammation. Non-steroidal antiinflammatory drugs such as aspirin inhibit cyclooxygenase (COX) activity and thus are believed to bring about their antiinflammatory action. Lipoxins, resolvins, protectins, and maresins There are two COX enzymes, the constitutively expressed COX-1 and the inducible enzyme COX-2. Different types of PGs are formed by the action of COX enzymes depending on the substrate fatty acid from which they are derived. Different types of PGs have different actions and sometimes diametrically opposite actions. There are three types of lipoxygenases that are present in only a few types of cells. 5-Lipoxygenase (5-LO), present in neutrophils, produces 5-hydroxyeicosatetraenoic acid (5-HETE), which is chemotactic for neutrophils and is converted into LTs. LTB4, a potent chemotactic and activator of neutrophils, induces aggregation and adhesion of leukocytes to vascular endothelium, generation of reactive oxygen species, and release of lysosomal enzymes. The cysteinyl-containing leukotrienes C4, D4, and E4 (LTC4, LTD4, and LTE4) induce vasoconstriction, bronchospasm, and vascular permeability in venules. LTs mediate their actions
Metabolism of essential fatty acids with specific reference to inflammation cis-Linoleic acid (LA, 18:2 u-6) and a-linolenic acid (ALA, 18:3 u-3) are essential nutrients because they cannot be synthesized by the human body and hence are called “essential fatty acids.” LA is converted to gamma-linolenic acid (GLA, 18:3, u-6) by the action of the enzyme D6 desaturase, and GLA is elongated to form di-homo-GLA (20:3, u-6), the precursor of the one series of prostaglandins. D6 desaturase is the rate-limiting step in the metabolism of essential fatty acids. Di-homo-GLA can also be converted to arachidonic acid (AA, 20:4, u-6) by the action of the enzyme D5 desaturase. AA forms the precursor of two series of prostaglandins, thromboxanes, and the four series LTs. ALA is converted to eicosapentaenoic acid (EPA, 20:5, u-3) by D6 and D5
Fig. 1. Metabolism of essential fatty acids.
U. N. Das / Nutrition 28 (2012) 951–958
by binding to cysteinyl leukotreine 1 (CysLT1) and CysLT2 receptors. Lipoxins (LXs) are generated from AA, resolvins from EPA and DHA, and protectins from by transcellular biosynthetic mechanisms involving two cell populations. Neutrophils produce intermediates in LX synthesis, and these are converted to LXs by platelets interacting with leukocytes. LXA4 and LXB4 are generated by the action of platelet 12-lipoxygenase on neutrophilderived LTA4. LXs have antiinflammatory actions [8] and are negative regulators of LT synthesis and thus resolve inflammation. An inverse relationship generally exists between LXs and LTs and the balance between these two molecules appears to be crucial in the determination of degree of inflammation and its final resolution [2–7]. Aspirin-triggered 15 epimer LXs (ATLs), resolvins, and protectins The formation of ATLs is a potent counterregulator of polymorphonuclear neutrophils (PMNs)-mediated injury and acute inflammation. Acetylated COX-2 enzyme of endothelial cells generates 15R-hydroxyeicosatetraenoic acid (15R-HETE) from AA that is converted by activated PMNs to the 15-epimeric LXs that have potent antiinflammatory properties [3–7]. This cross-talk between endothelial cells and PMNs, leading to the formation of 15R-HETE and its subsequent conversion to 15-epimeric LXs by aspirin-acetylated COX-2, is a protective mechanism to prevent local inflammation by regulating the motility of PMNs, eosinophils, and monocytes [6,7]. Endothelial cells also oxidize AA, EPA, and DHA via the P450 enzyme system to form various hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids such as 11,12-epoxyeicosatetraenoic acid(s) that possess antiinflammatory actions [7–12]. Akin to the formation of 15R-HETE and 15-epimeric LXs from AA, similar compounds are also formed from EPA and DHA. In the presence of aspirin, activated COX-2 of human endothelial cells converts EPA to 18R-HEPE, 18-HEPE, and 15R-HEPE. Activated human PMNs, in turn, converted 18R-HEPE to 5,12,18R-triHEPE and 15R-HEPE to 15-epi-LXA5 by their 5-lipoxygenase. Both 18RHEPE and 5,12,18R-triHEPE inhibited LTB4-stimulated PMN transendothelial migration. 5,12,18R-triHEPE effectively competed with LTB4 for its receptors and inhibited PMN infiltration and suppressed LT-mediated inflammation [4,5,7,13]. The conversion of EPA by human endothelial cells with upregulated COX-2 treated with ASA of EPA to 15-epi-LX also termed aspirin-triggered LX (ATL) and to 18R-HEPE and 15RHEPE is interesting. These compounds, in turn, are used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15RLX(5) and 5,12,18R-triHEPE, which are potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analog > 5,12,18R-triHEPE > 18R-HEPE). The formation of these bioactive lipid mediators via COX-2-nonsteroidal antiinflammatory drug-dependent oxygenations and cell-cell interactions inhibits inflammation [7,13]. COX-2 in the presence of aspirin can transform enzymatically DHA to 17R series of hydroxy DHAs that, in turn, are converted enzymatically by PMNs to di- and trihydroxy-containing docosanoids [7,13,14]. The conversion of DHA by leukocytes, brain, and glial cells to 17S-hydroxy-containing docosanoids denoted as docosatrienes (the main bioactive member of the series was 10,17S-docosatriene) and 17S series resolvins reduces leukocyte infiltration in vivo and blocks cytokine production by glial cells that may explain the antiinflammatory actions of DHA.
953
Similar small molecular weight compounds are also generated from AA, EPA, and DHA: 15R-hydroxy-containing compounds from AA, 18R series from EPA, and 17R-hydroxy series from DHA that have antiinflammatory actions, resolve inflammation, and hence are called “resolvins.” Resolvins inhibited cytokine generation, leukocyte recruitment, leukocyte diapedesis, and exudate formation. The formation of resolvins from acetylated COX-2 are generated via transcellular biosynthesis (e.g., due to cell-cell communication between endothelial cells and PMNs), and their main purpose is to suppress inflammation. Resolvins inhibited brain ischemia-reperfusion injury [14]. It is possible that lipoxins, resolvins, and protectins (docosanoids are also called as protectins because they have neuroprotective actions) behave as endogenous antiinflammatory and cytoprotective molecules. The general cytoprotective properties that have been attributed to AA, EPA, and DHA can be related to their conversion to lipoxins, resolvins, and docosanoids (protectins) (Figs. 2-4 show the formation of lipoxins, resolvins, and protectins from their precursors). Hence, any defect in the synthesis of lipoxins, resolvins, and protectins or their inappropriate degradation could lead to perpetuation of inflammation as seen in MS and other inflammatory conditions.
Anti-inflammatory molecule lipoxin A4 is detectable in urine LX4, generated by LO transformation of AA, possess potent anti-inflammatory activity in vivo and temporal biosynthesis of LX, concurrent with spontaneous resolution, has been observed during exudate formation [9–11]. LXs, resolvins, protectins, and maresins are detectable in the plasma. However, if any compound that one wishes to use as a biomarker of a disease process can be detected in the urine, then it will be feasible to bring such a marker to the clinic rather rapidly. Recently, a new extraction technique, more selective for LX, which abolishes background contamination and minimizes the unspecific reading, was developed. This new method showed that urine from healthy subjects contains LXA4 [15]. Subsequently, it was shown [16] that exercise, which is antiinflammatory in nature [17], significantly increased urinary excretion in healthy volunteers (0.061 0.023 versus 0.113 0.057 ng/mg creatinine; P ¼ 0.028). These findings confirm that alterations in the urinary excretion of LXA4 can be used as a reflection of changes in its (LXA4) formation to monitor changes in the inflammatory lesions
Fig. 2. Scheme showing the formation of lipoxin A4 from arachidonic acid.
954
U. N. Das / Nutrition 28 (2012) 951–958
Fig. 3. Scheme showing the formation of various lipoxins from arachidonic acid as a result of intercellular communication, coordination, and cooperation.
and antiinflammatory nature of exercise could be attributed, in part, to enhanced formation of LXA4. In a further extension of this work, it was reported that urinary levels of LXA4 were decreased, whereas that of cysteinyl leukotrienes increased in volunteers aged 26 to over 100 y, leading to a profound unbalance of the LXA(4)/cysteinyl leukotrienes ratio that may be considered an index of the endogenous antiinflammatory potential [18]. These results suggest that endogenous antiinflammatory mechanisms become less efficient with age that could result in increased susceptibility to inflammatory disorders with advancing age. A recent study revealed that in HSP nephritis, concordant with the gradually increased severity of the disease, the expressions of 15-lipoxygenase and the levels of urinary LXA4 gradually decreased and the expressions of LTC4 synthase and the urinary
LTE4 and LTB4 gradually increased [19]. These data suggest that LTs play a proinflammatory role and insufficiency of LXA4 may be responsible for the severity of the illness. Absence or decreased levels of LXA4 that act as a “stop signal” of inflammatory process may be responsible for the continued inflammation. Based on these findings, measurement of plasma and urinary LXs and LTs and possibly other eicosanoids could be used as a marker of inflammatory process in various organs in the body. Because there is a good correlation between plasma (blood) and urinary levels of LXs and LTs and the degree of inflammatory process, measurement of plasma and urinary levels of various eicosanoids may serve as a marker of inflammation and changes in their respective levels could predict the progression, resolution, and continuation of the inflammatory process and diseases in which inflammation plays a significant role such as MS.
Fig. 4. Scheme showing the formation of resolvin E1 from EPA.
U. N. Das / Nutrition 28 (2012) 951–958
Anti-inflammatory cytokines IL-4 and IL-10 enhance LXA4 synthesis In this context, it is noteworthy that antiinflammatory cytokines IL-4 and IL-10 trigger the conversion of AA, EPA, and DHA to lipoxins, resolvins, protectins, and maresins, suggesting a mechanism by which they are able to suppress inflammation [20]. For example, IL-4 up-regulated [it may be noted here that 15-S-HETE (a 15-LO product) and lipoxins (interaction products between 5-LO and either 12-LO or 15-LO) counteract the proinflammatory actions of LTs] 15-LO gene expression in human leukocytes. Glomerular 12/15-LO mRNA increased significantly over controls 24 and 48 h after nephrotoxic serum injection and then decreased at 72 h. RNA from nephrotoxic-serum-injected glomeruli contained higher levels of 12/15-LO mRNA than that from unstimulated peripheral leukocytes, suggesting that 12/15LO transcription is up-regulated locally in native and/or infiltrating glomerular cells. Glomerular IL-4 mRNA increased markedly 16 h postnephrotoxic serum injection and was then reduced, suggesting a potential role for T-cell-derived IL-4 in directing the expression of 12/15-LO during glomerulonephritis. This suggested tandem-regulated in vivo gene expression for IL-4 and LO, both of which promote counterinflammatory influences in immune-complex-mediated injury and it is reasonable to predict that such events may also occur in MS. Balance between LXA4 and LTs determines the degree of inflammation The 5-lipoxygenated metabolites of AA, the LTs, are major mediators of early glomerular hemodynamic and structural deterioration during experimental glomerulonephritis that are generated largely by infiltrating leukocytes but can also occur by intrinsic glomerular cells via transcellular metabolism of intermediates. In animal models of glomerulonephritis and other renal pathologic states, LTs have been shown to exert adverse effects in the glomerulus. LTB4 augments neutrophil infiltration, and LTC4 and LTD4 mediate potent vasoconstrictor effects on the glomerular microcirculation. Selective blockade of the 5lipoxygenase pathway produced a significant amelioration of the deterioration of renal hemodynamic and structural parameters. On the other hand, 15-S-HETE, the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of AA, are also generated in the course of glomerular injury that antagonizes LT-induced neutrophil chemotaxis, and lipoxin A4 antagonized the effects of LTD4 and LTC4 on the glomerular microcirculation. Thus, the contrasting effects of 5- and 15lipoxygenase products represent endogenous pro- and antiinflammatory influences that ultimately determine and regulate the extent and severity of glomerular inflammation [21–24]. These results are in favor of the proposal that antiinflammatory cytokines IL-4 and IL-10 induce the expression and synthesis of antiinflammatory lipid mediators lipoxins, resolvins, protectins, and maresins in addition to their ability to suppress the production of proinflammatory cytokines such as IL-2, IL-6, TNF-a, MIF, HMGB1, and LTs. PUFAs and lipoxins bind to G-protein-coupled receptors to suppress inflammation It is noteworthy that monocytes and macrophages express an extensive repertoire of G-protein-coupled receptors (GPCRs) that regulate inflammation and immunity. A number of GPCRs
955
(e.g., Edg5, P2ry2, and 6) have been reported to be expressed by macrophages and two cell types closely related to macrophages (osteoclasts and dendritic cells), whereas Gpr84 expression was largely restricted to macrophage populations and granulocytes [25]. It is now apparent that many PUFAs, especially AA, EPA, and DHA, and their metabolites such as eicosanoids, lipoxins, resolvins, protectins, and maresins, also function directly as agonists at a number of GPCRs. Tissue distribution studies and siRNA knockdown experiments have indicated key roles for these GPCRs in glucose homeostasis, adipogenesis, leukocyte recruitment, and inflammation [26]. A recent study showed that the G-protein-coupled receptor 120 (GPR120) functions as a u-3 fatty acid receptor/sensor. Stimulation of GPR120 with u3 fatty acids (EPA and DHA) induced broad antiinflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects were abrogated by GPR120 knockdown. The u-3 fatty acid treatment not only inhibited inflammation but also enhanced systemic insulin sensitivity in wild-type mice, but was without effect in GPR120 knockout mice. These results suggest that GPR120 is a functional u-3 fatty acid receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation [27]. Thus, it is likely that PUFAs and their antiinflammatory products such as lipoxins, resolvins, protectins, and maresins inhibit the production of various proinflammatory molecules including MIF and HMGB1 and thus suppress inflammation in diseases such as MS (Fig. 5). The human brain is rich in AA, EPA, and DHA (DHA > AA > EPA), which constitute as much as 30% to 50% of the total fatty acids in the brain, where they are predominantly associated with membrane phospholipids. Nerve growth cones are highly enriched with AA-releasing phospholipases, which have been implicated in neurite outgrowth. Cell membrane expansion occurs through the fusion of transport organelles with plasma membrane, and syntaxin 3, a plasma membrane protein that is important in the growth of neurites, is a direct target for AA, DHA, and other PUFAs. It has been shown that AA, DHA, and other PUFAs but not saturated and monounsaturated fatty acids activate syntaxin 3. Syntaxin1 that is specifically involved in fast calcium-triggered exocytosis of neurotransmitters is sensitive to AA, suggesting that AA is involved in both exocytosis of neurotransmitters and neurite outgrowth. SNAP25 (synaptosomal-associated protein of 25 kDa), a syntaxin partner implicated in neurite outgrowth, interacts with syntaxin 3 only in the presence of AA that allowed the formation of the binary syntaxin 3-SNAP25 complex. AA stimulated syntaxin 3 to form the ternary SNARE complex (soluble N-ethylmaleimide-sensitive factor attachment protein receptor), which is needed for the fusion of plasmalemmal precursor vesicles into the cell surface membrane that leads to membrane fusion. The intrinsic tyrosine fluorescence of syntaxin 3 showed marked changes on the addition of AA, DHA, LA, and ALA, whereas saturated and monounsaturated (oleic acid) fatty acids were ineffective. Thus, AA and DHA change the a-helical syntaxin structure to expose the SNARE motif for immediate SNAP25 engagement that facilitates neurite outgrowth [28,29]. In addition, PUFAs have the ability to modulate the actions of various neurotransmitters and hypothalamic peptides (see ref. [30]). One major action of AA, EPA, and DHA in the brain could be not only to form precursors to antiinflammatory lipoxins, resolvins, protectins, and maresins but also to enhance synaptic formation and neurite outgrowth and to facilitate neurotransmission that are impaired in MS.
956
U. N. Das / Nutrition 28 (2012) 951–958
Fig. 5. Scheme showing the role of prostaglandins and leukotrienes and lipoxins in MS and its resolution. () Inhibition or suppression of action; (þ) activation or enhancement of action. There are three classes of phospholipases that control the release of AA and other PUFAs: calcium-independent PLA2 (iPLA2), secretory PLA2 (sPLA2), and cytosolic PLA2 (cPLA2) [38]. Each class of PLA2 is further divided into isoenzymes for which there are 10 for mammalian sPLA2, at least 3 for cPLA2, and 2 for iPLA2. During the early phase of inflammation, COX-derived PGs and lipoxygenase-derived LTs initiate exudate formation and inflammatory cell influx [9,39]. TNF-a causes an immediate influx of neutrophils concomitant with PGE2 and LTB4 production, whereas during the phase of resolution of inflammation an increase in LXA4 (lipoxin A4), PGD2, and its product 15deoxyD12-14PGJ2 formation occurs that induces the resolution of inflammation with a simultaneous decrease in PGE2 synthesis that stops neutrophil influx and enhances phagocytosis of debris [40,41]. Thus, there are two waves of release of AA and other PUFAs: one at the onset of inflammation that causes the synthesis and release of PGE2 and a second at resolution for the synthesis of antiinflammatory PGD2, 15deoxyD12-14PGJ2, and lipoxins that are necessary for the suppression of inflammation. Thus, COX-2 enzyme has both harmful and useful actions by virtue of its ability to give rise to proinflammatory and antiinflammatory PGs and LXs. Increased type VI iPLA2 protein expression was the principal isoform expressed from the onset of inflammation up to 24 h, whereas type IIa and V sPLA2 were expressed from the beginning of 48 h until 72 h, whereas type IV cPLA2 was not detectable during the early phase of acute inflammation but increased progressively during resolution, peaking at 72 h. This increase in type IV cPLA2 was mirrored by a parallel increase in COX-2 expression [42]. The increase in cPLA2 and COX-2 occurred in parallel, suggesting a close enzymatic coupling between these two. Thus, there is a clear-cut role for different types of PLA2 in distinct and different phases of inflammation. Selective inhibition of cPLA2 resulted in the reduction of pro-inflammatory molecules PGE2, LTB4, IL-1b, and platelet-activating factor (PAF). Furthermore, inhibition of types IIa and V sPLA2 not only decreased PAF and LXA4 (lipoxin A4) but also resulted in a reduction in cPLA2 and COX-2 activities. These results suggest that sPLA2-derived PAF and LXA4 induce COX-2 and type IV cPLA2. IL-1b induced cPLA2 expression, suggesting that IL-1 not only induces inflammation but also enhances cPLA2 expression to initiate the resolution of inflammation [43,44]. Synthetic glucocorticoid dexamethasone inhibited both cPLA2 and sPLA2 expression, whereas type IV iPLA2 expression is refractory to its suppressive actions [42,45,46]. Activated iPLA2 contributes to the conversion of inactive proIL-1b to active IL-1b that, in turn, induces cPLA2 expression, which is necessary for resolution of inflammation. LXs, especially LXA4, inhibit TNF-a-induced production of ILs, promote TNF-a mRNA decay, TNF-a secretion, and leukocyte trafficking, and thus attenuated inflammation. In a recent study [47], it was observed that in a mouse model of spinal cord injury (SCI) two cytosolic forms [calcium-dependent PLA2 group IVA (cPLA2 GIVA) and calcium-independent PLA2 group VIA (iPLA2 GVIA)], and a secreted form [secreted PLA2 group IIA (sPLA2 GIIA)] are up-regulated and these PLA2s play differing roles. cPLA2 GIVA mediated protection, whereas sPLA2 GIIA and, to a lesser extent, iPLA2 GVIA were found to be detrimental. Furthermore, completely blocking all three PLA2s worsened the outcome, whereas partial inhibition of all the three PLA2s showed the most beneficial action. It was noted that enhanced expression of cPLA2 mediated its beneficial effects via the prostaglandin EP1 receptor. These results suggest that drugs that inhibit detrimental forms of PLA2 (sPLA2 and iPLA2) and up-regulation of the protective form (cPLA2) is likely to be useful in the treatment of SCI. For further details, see text.
Hypothesis: A deficiency of LXA4 and excess of LTs and PGE2 may be responsible for MS Based on the evidence presented above and the role of LXA4 and LTs and PGE2 in inflammation, it is quite logical to suggest that a deficiency of LXA4 and other PGs that have
antiinflammatory actions and/or an excess of LTs and PGE2 initiate and perpetuate inflammation in MS. Because it is possible to estimate these compounds in the plasma, urine, and possibly the cerebrospinal fluid (CSF), I propose that progression and flares of MS are due to decreased production of LXA4 and enhanced production of LTs by the neurons and/or infiltrating
U. N. Das / Nutrition 28 (2012) 951–958
leukocytes and macrophages. These molecules can be detected and estimated in the plasma, urine, and possibly the CSF [15,16, 18]. Furthermore, the plasma, urinary, and CSF levels of LXA4 and LTs may also be used to predict prognosis and response to treatment. If the plasma, urinary, and CSF LXA4 levels revert to normal or are slowly increasing with and without decrease in the plasma, urinary, and CSF levels of LTs, it can be considered an indication that the patient is responding to treatment and MS is ameliorating. The urinary levels of LXA4 and LTs can be compared to their plasma and CSF concentrations and to the clinical picture and Expanded Disability Status Scale, Multiple Sclerosis Functional Composite (or the Scripps Rating Scale), Cognitive Function Tests, and various imaging technologies such as computed tomography and magnetic resonance imaging scans of the brain to know the progress of MS. Because resolvins, protectins, and maresins are also antiinflammatory lipid molecules derived from EPA and DHA and have a role in the resolution of inflammation, it is predicted that they may also have the same significance as that of lipoxins in MS. Hence, it is worthwhile to measure the plasma, urinary, and CSF levels of resolvins, protectins, and maresins in addition to lipoxins in the plasma, urine, and CSF of patients with MS to predict prognosis and response to treatment. A decrease in their levels in the plasma, urine, and CSF indicates continued inflammation and damage to various neurological structures in the brain, whereas enhancement in their levels indicates resolution of inflammation and amelioration of MS.
957
decreased formation of lipoxins, resolvins, protectins, and maresins may have exacerbated EAE/MS. These results indicate that lipids play a significant role in MS [33]. Lipoxins, resolvins, protectins, and maresins are not only antiinflammatory in nature but also enhance wound healing, resolve inflammation, and have cytoprotective and neuroprotective actions [2–7]. Hence, when the local concentrations of lipoxins, resolvins, protectins, and maresins are low, which could be secondary to reduced levels of PUFAs, it would lead to continued inflammation and neuronal damage, whereas when their (PUFAs, lipoxins, resolvins, protectins, and maresins) levels are enhanced, inappropriate inflammation will be suppressed, leading to healing and neuronal protection. In addition, lipoxins, resolvins, protectins, and maresins enhance stem cell survival, proliferation, and neuronal differentiation [34–37] that could aid in the healing of the neuronal damage that occurs in MS and augment the recovery process. This implies that methods designed to enhance the levels of PUFAs, and their anti-inflammatory products lipoxins, resolvins, protectins, and maresins, or administration of synthetic analogs of lipoxins, resolvins, protectins, and maresins may be of significant benefit in the prevention and management of MS. Acknowledgment Dr. U. N. Das is in receipt of the Ramalingaswami fellowship of the Department of Biotechnology, India for the tenure of this study.
Involvement of eicosanoids and lipoxins, resolvins, protectins, and maresins in MS
References
Studies of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have shown that autoreactive T cells secreting IL-17 (TH17 cells) and IFN-g (TH1 cells) are involved in EAE/MS pathogenesis. Using an AA-cascade-targeted lipidomics approach, it was reported that microsomal PGE synthase 1 (mPGES-1) plays a key role in the inflammation seen in EAE. PGD2 was produced constitutively in the spinal cord of naive mice, whereas induction of EAE lesions in the production of PGE2 was favored and PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. PGD2, PGI2, and 5-LO metabolites such as lipoxins, resolvins, and protectins have antiinflammatory action (Fig. 5). Furthermore, mPGE-1/ mice showed less severe symptoms of EAE and lower production of IL-27 and IFN-g than mPGEs-1þ/þ mice. Immunohistochemistry on the central nervous system of EAE mice and MS patients revealed overt expression of mPGES-1 protein in microglia/macrophages [31]. It was noted that of all the eicosanoids examined, only PGE2 was significantly elevated in the spinal cords of EAE mice. PGE2 produced by microglia/ macrophages in inflammatory foci may aggravate EAE by promoting the differentiation of TH1 and the expression of TH17 cells through EPs (eicosanoid receptors). Furthermore, it was noted that in PGI2 that enhances endothelial barrier function and thus protects mice from EAE, production is decreased, whereas that of PGD2, an antiinflammatory molecule, was reduced [31]. A significant suppression of 5-LO metabolites was noted and 5-LO/ mice developed more severe EAE than control wild-type mice [32], suggesting that both increased formation of PGE2 and decreased formation of 5-LO products such as lipoxins, resolvins, protectins, and maresins play a significant role in EAE and MS. Unfortunately, in this study [31], lipoxins, resolvins, protectins, and maresins were not measured. It was reported that 12/15-LO deficiency conferred more severe EAE pathology [32], suggesting that
[1] Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 2009;65:239–48. [2] Das UN. Clinical laboratory tools to diagnose inflammation. Adv Clin Chem 2006;41:189–229. [3] Claria J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci USA 1995;92:9475–9. [4] Das UN. Essential fatty acids: Biochemistry, physiology, and pathology. Biotechnol J 2006;1:420–39. [5] Das UN. Essential fatty acidsda review. Curr Pharmaceutical Biotechnol 2006;7:467–82. [6] Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation signals in resolution. Nat Immunol 2001;2:612–9. [7] Das UN. Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation. J Inflammation Res 2010;3:143–70. [8] Zordoky BN, El-Kadi AO. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol Ther 2010;125:446–63. [9] Nithipatikom K, Gross GJ. Review article: epoxyeicosatrienoic acids: novel mediators of cardioprotection. J Cardiovasc Pharmacol Ther 2010;15:112–9. [10] Campbell WB, Fleming I. Epoxyeicosatrienoic acids and endotheliumdependent responses. Pflugers Arch 2010;459:881–95. [11] Arnold C, Konkel A, Fischer R, Schunck WH. Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol Rep 2010;62:536–47. [12] Gao L, Yin H, Milne GL, Porter NA, Morrow JD. Formation of F-ring isoprostane-like compounds (F3-isoprostanes) in vivo from eicosapentaenoic acid. J Biol Chem 2006;281:14092–9. [13] Serhan CN, Clish CB, Brannon J, Colgan SP, Gronert K, Chiang N. Antimicroinflammatory lipid signals generated from dietary N-3 fatty acids via cyclooxygenase-2 and transcellular processing: a novel mechanism for NSAID and N-3 PUFA therapeutic actions. J Physiol Pharmacol 2000;51(4 Pt 1):643–54. [14] Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem 2003;278:14677–87. [15] Romano M, Luciotti G, Gangemi S, Marinucci F, Prontera C, D’Urbano E, et al. Urinary excretion of lipoxin A(4) and related compounds: development of new extraction techniques for lipoxins. Lab Invest 2002;82:1253–4.
958
U. N. Das / Nutrition 28 (2012) 951–958
[16] Gangemi S, Luciotti G, D’Urbano E, Mallamace A, Santoro D, Bellinghieri G, et al. Physical exercise increases urinary excretion of lipoxin A4 and related compounds. J Appl Physiol 2003;94:2237–40. [17] Das UN. Anti-inflammatory nature of exercise. Nutrition 2004;20:323–6. [18] Gangemi S, Pescara L, D’Urbano E, Basile G, Nicita-Mauro V, Davı G, et al. Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels. Exp Gerontol 2005;40:612–4. [19] Wu SH, Liao PY, Yin PL, Zhang YM, Dong L. Inverse temporal changes of lipoxin A4 and leukotrienes in children with Henoch-Schönlein purpura. Prostaglandins Leukot Essent Fatty Acids 2009;80:177–83. [20] Katoh T, Lakkis FG, Makita N, Badr KF. Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Kidney Int 1994;46:341–9. [21] Nassar GM, Badr KF. Role of leukotrienes and lipoxygenases in glomerular injury. Miner Electrolyte Metab 1995;21:262–70. [22] Papayianni A, Serhan CN, Phillips ML, Rennke HG, Brady HR. Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis. Kidney Int 1995;47:1295–302. [23] O’Meara YM, Brady HR. Lipoxins, leukocyte recruitment and the resolution phase of acute glomerulonephritis. Kidney Int Suppl 1997;58:S56–61. [24] Wu SH, Liao PY, Yin PL, Zhang YM, Dong L. Elevated expressions of 15lipoxygenase and lipoxin A4 in children with acute poststreptococcal glomerulonephritis. Am J Pathol 2009;174:115–22. [25] Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, et al. Expression analysis of G protein-coupled receptors in mouse macrophages. Immunome Res 2008;4:5. [26] Milligan G, Stoddart LA, Brown AJ. G protein-coupled receptors for free fatty acids. Cell Signal 2006;18:1360–5. [27] Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010;142:687–98. [28] Darios F, Davletov B. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 2006;440:813–7. [29] Calderon F, Kim H-Y. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem 2004;90:979–88. [30] Das UN. Metabolic syndrome pathophysiology: Role of essential fatty acids. Ames, IA: Wiley-Blackwell; 2010. [31] Kihara Y, Matsushita T, Kita Y, Uematsu S, Akira S, Kira J, et al. Targeted lipidomic reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad Sci USA 2009;106:21807–12. [32] Emerson MR, LeVine SM. Experimental allergic encephalomyelitis is exacerbated in mic2 deficient for 12/15-lipoxygenase or 5-lipoxygenase. Brain Res 2004;1021:140–5.
[33] Kanter JL, Narayana S, Ho PP, Catz I, Warren KG, Sobel RA, et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 2006;12:138–43. nchez-Ruiz A, Benton HP, Trauger SA, [34] Yanes O, Clark J, Wong DM, Patti GJ, Sa et al. Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol 2010;6:411–7. [35] Bazan NG. The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling. Cell Mol Neurobiol 2006;26:901–13. [36] Das UN. Influence of polyunsaturated fatty acids and their metabolites on stem cell biology. Nutrition 2011;27:21–5. [37] Das UN. Molecular Basis of Health and Disease. New York: Springer; 2011. [38] Bonventre JV. Phospholipase A2 and signal transduction. J Am Soc Nephrol 1992;3:128–50. [39] Das UN. Radiation resistance, invasiveness and metastasis are inflammatory events that could be suppressed by lipoxin A(4). Prostaglandins, leukotrienes, and essential fatty acids 2012;86:3–11. [40] Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol 2000;164:1663–7. [41] Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 1999;5:698–701. [42] Gilroy DW, Newson J, Sawmynaden P, Willoughby DA, Croxtall JD. A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation. FASEB J 2004;18:489–98. [43] Cominelli F, Nast CC, Llerena R, Dinarello CA, Zipser RD. Interleukin 1 suppresses inflammation in rabbit colitis. Mediation by endogenous prostaglandins. J Clin Invest 1990;85:582–6. [44] Schwab JH, Anderle SK, Brown RR, Dalldorf FG, Thompson RC. Pro- and anti-inflammatory roles of interleukin-1 in recurrence of bacterial cell wall-induced arthritis in rats. Infect Immun 1991;59:4436–42. [45] Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, et al. Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002;196:1025–37. [46] Croxtall JD, Choudhury Q, Tokumoto H, Flower RJ. Lipocortin-1 and the control of arachidonic acid release in cell signalling. Glucocorticoids inhibit G protein-dependent activation of cPLA2 activity. Biochem Pharmacol 1995;50:465–74. [47] Lo’pez-Vales R, Ghasemlou N, Redensek A, Kerr BJ, Barbayianni E, Antonopoulou G, et al. Phospholipase A2 superfamily members play divergent roles after spinal cord injury. FASEB J 2011;25:4240–52.