Emerging roles of secreted phospholipase A2 enzymes: The 3rd edition

Biochimie xxx (2014) 1e9

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Review

Emerging roles of secreted phospholipase A2 enzymes: The 3rd edition* Makoto Murakami a, b, *, Yoshitaka Taketomi a, Yoshimi Miki a, Hiroyasu Sato a, rard Lambeau c Kei Yamamoto a, Ge a

Lipid Metabolism Project, The Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan Institut de Pharmacologie Mol eculaire et Cellulaire, UMR 7275, Centre National de la Recherche Scientifique e Universit e Nice Sophia Antipolis, Valbonne 06560, France b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 24 July 2014 Accepted 5 September 2014 Available online xxx

Within the phospholipase A2 (PLA2) superfamily, secreted PLA2 (sPLA2) enzymes comprise the largest family that contains 11 to 12 mammalian isoforms with a conserved His-Asp catalytic dyad. Individual sPLA2s exhibit unique tissue and cellular localizations and specific enzymatic properties, suggesting distinct biological roles. Individual sPLA2s are involved in diverse biological events through lipid mediator-dependent or -independent processes and act redundantly or non-redundantly in a given microenvironment. In the past few years, new biological aspects of sPLA2s have been clarified using their transgenic and knockout mouse lines in combination with mass spectrometric lipidomics to unveil their target substrates and products in vivo. In the 3rd edition of this review series, we highlight the newest understanding of the in vivo functions of sPLA2s in pathophysiological conditions in the context of immunity and metabolism. We will also describe the latest knowledge on PLA2R1, the best known sPLA2 receptor, which may serve either as a clearance or signaling receptor for sPLA2 or may even act independently of sPLA2 function. te  française de biochimie et biologie Mole culaire (SFBBM). All rights Ó 2014 Elsevier B.V. and Socie reserved.

Keywords: Fatty acid Lipid mediator Phospholipid Prostaglandin Secreted phospholipase A2

1. Introduction The secreted phospholipase A2 (sPLA2) family consists of low molecular mass, Ca2þ-requiring enzymes with a conserved His-Asp catalytic dyad. The 12 mammalian sPLA2s (IB, IIA, IIC, IID, IIE, IIF, III, V, X, XIIA, XIIB and otoconin-95) are subdivided into the group I/II/ V/X structural collection (I, II, V and X) and two other atypical Abbreviations: DC, dendritic cell; DHA, docosahexaenoic acid; DP1, D prostanoid receptor 1; FcεRI, high affinity receptor for IgE; IL, interleukin; LDL, low-density lipoprotein; L-PGDS, lipocalin type-prostaglandin D synthase; LT, leukotriene; MC, mast cell; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PGD2, prostaglandin D2; PLA2, phospholipase A2; PLA2R1, sPLA2 receptor; PS, phosphatidylserine; SCF, stem cell factor; sPLA2, secreted PLA2; Tg, transgenic. * This work was supported by grant-in-aid for scientific research from the Ministry of Education, Science, Culture, Sports and Technology of Japan and CREST from the Japan Science and Technology Agency. In the interest of brevity, we have referenced other reviews whenever possible and apologize to the authors of the numerous original papers that were not explicitly cited. * Corresponding author. Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Tel.: þ81 5316 3228; fax: þ81 5316 3125. E-mail address: [email protected] (M. Murakami).

structural collections (III and XII) [1]. The level of identity between any two paralogs of sPLA2 is lower than 51%, suggesting that these enzymes are not closely related isoforms and should exert different functions. Furthermore, several inhibitors have been developed against various sPLA2s from the group I/II/V/X structural collection, but none of these inhibitors are active against the atypical group III and XIIA enzymes. Accordingly, recent studies using genemanipulated mice for individual sPLA2s have begun to reveal their distinct and unique roles in various biological events, including digestion, inflammation, atherosclerosis, host defense, reproduction, and so on. In principle, individual sPLA2s exert their specific functions by producing lipid mediators, by altering membrane phospholipid composition, by degrading foreign phospholipids in microorganisms or diets, or by modifying extracellular non-cellular lipid components (lipoproteins, pulmonary surfactant or microvesicles) in response to given microenvironmental cues. The biological effects of sPLA2s may also be driven or counterregulated by binding to soluble and membrane proteins including the M-type sPLA2 receptor (PLA2R1). Current understanding of the in vivo functions of sPLA2s was summarized in our previous Biochimie reviews in 2010 [2] and 2013 [3] as well as in other recent

http://dx.doi.org/10.1016/j.biochi.2014.09.003  te  française de biochimie et biologie Mole culaire (SFBBM). All rights reserved. 0300-9084/Ó 2014 Elsevier B.V. and Socie

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reviews [4e6]. After publishing these reviews, there have been considerable advances in the sPLA2 research field. Here, we will make an overview of several novel biological roles of sPLA2s and the underlying lipid pathways as revealed by sophisticated knockout and lipidomics studies in the last two years. 2. Group III sPLA2, an “anaphylactic sPLA2” that facilitates mast cell maturation It has been proposed that sPLA2s, after being secreted, may act on neighboring cells or extracellular phospholipids to augment lipid mediator synthesis. However, this idea has yet to gain traction because in vivo evidence was largely lacking. Recently, group III sPLA2 (sPLA2-III) has been shown to utilize a unique, paracrine prostaglandin D2 (PGD2) pathway to facilitate mast cell (MC) maturation and thereby allergy, thus providing a rationale for the long-lasting question on the role of sPLA2 as a paracrine eicosanoid mobilizer [7]. Cross-linking of the high-affinity IgE receptor FcεRI on MCs with IgE and antigen initiates the release of allergic mediators that induce immediate hypersensitivity [8]. Microenvironment-based alterations in MC phenotypes affect the susceptibility to allergy [9], yet the mechanisms underlying the proper maturation of MCs toward an allergy-sensitive phenotype are poorly understood. Mammalian sPLA2-III is the sole mammalian homolog of bee venom sPLA2, a potent inducer of anaphylaxis [10], raising the possibility that sPLA2-III, beyond its crucial role in male reproduction [11], may act as an endogenous regulator of MCs. In fact, sPLA2III is stored in and released from MC granules, and MC-associated passive and active anaphylactic responses are markedly attenuated in Pla2g3/ mice and conversely augmented in Pla2g3transgenic (Tg) mice [7]. Interleukin (IL)-3-dependent bone marrow-derived MCs prepared from Pla2g3/ mice fail to reconstitute the anaphylactic response after transfer into MC-deficient

KitW-sh/W-sh mice, indicating that the defects caused by sPLA2-III deficiency is MC-autonomous. Tissue MCs in Pla2g3/ mice are numerically normal, but morphologically and functionally immature. Pla2g3/ BMMCs exhibit defective fibroblast-directed maturation and thereby IgE-dependent and even -independent activation in ex vivo culture. Strikingly, similar MC abnormalities are also seen in mice lacking lipocalin-type PGD2 synthase (L-PGDS) or those lacking the PGD2 receptor DP1, suggesting their functional linkage in a common signaling pathway. Indeed, genetic or pharmacological ablation of DP1 in MCs or L-PGDS in fibroblasts phenocopies that of sPLA2-III in MCs in terms of defective MC maturation and anaphylaxis. Moreover, inhibition of either PLA2G3, L-PGDS or DP1 prevents the maturation of human MCs in culture. Taken together, sPLA2-III secreted from immature MCs is coupled with fibroblastic L-PGDS to provide microenvironmental PGD2, which in turn promotes MC maturation via DP1 induced on MCs (Fig. 1) [7,12]. The sPLA2-III/L-PGDS/DP1 axis is a novel lipid-orchestrated mechanism, uncovering a missing microenvironmental cue underlying the proper maturation of MCs, a new aspect of PGD2-DP1 signaling in promoting MC maturation and thereby allergy, and a novel function of stem cell factor (SCF), a stromal cytokine that triggers this unique lipid pathway by inducing sPLA2-III secretion from MCs. Given that sPLA2-III, an “anaphylactic sPLA2”, is insensitive to all known sPLA2 inhibitors, a new agent that would specifically inhibit this atypical sPLA2 may be useful for the treatment of patients with mast cell-associated allergic and other diseases. 3. Group IID sPLA2, a “resolving sPLA2” that sequesters inflammation Resolution of inflammation is an active process partly mediated by anti-inflammatory or pro-resolving lipid mediators [13]. While

Fig. 1. sPLA2-III promotes mast cell maturation and allergy by driving a paracrine PGD2 loop. Interaction between MCs and fibroblasts is essential for proper MC maturation in tissues. sPLA2-III, an “anaphylactic sPLA2” that is released from immature MCs, is coupled with fibroblastic L-PGDS to promote sustained production of PGD2 in this microenvironment, which in turn acts on DP1 on MCs to facilitate MC maturation. Mature MCs have more histamine granules and surface FcεRI and express higher levels of cytosolic PLA2 (cPLA2a) and hematopoietic PGDS (H-PGDS). Cross-linking of FcεRI with multivalent antigen (Ag) elicits explosive activation of mature MCs, which leads to pro-allergic histamine release and thereby allergic reactions. On the other hand, cPLA2a/H-PGDS-driven immediate production of PGD2 by mature MCs is anti-allergic [7].

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different PLA2s have been implicated in the promotion of inflammation through mobilizing arachidonic acid-derived lipid mediators, the molecular entity of the PLA2 subtype(s) participating in the release of pro-resolving lipid mediators, such as resolvins and protectins, have remained unknown. Group IID sPLA2 (sPLA2-IID) was initially identified as an isoform structurally most similar to the classical “inflammatory sPLA2” group IIA (sPLA2-IIA) [14,15]. Administration of an artificial sPLA2-IID-Fc protein attenuates autoimmune diseases in mice through unknown mechanisms [16]. It has recently been shown that sPLA2-IID is preferentially expressed in CD11cþ dendritic cells (DCs) in secondary lymphoid organs and has a pro-resolving function by driving the production of pro-resolving lipid mediators [17]. In a model of Th1-dependent hapten-induced contact dermatitis, resolution, not propagation, of inflammation is compromised in skin and regional lymph nodes of Pla2g2d/ mice [17]. In Pla2g2d/ lymph nodes, the immune balance shifts toward a proinflammatory state over an anti-inflammatory state. Bone marrow-derived DCs from Pla2g2d/ mice are spontaneously activated and elicit skin edema after intravenous transfer into mice. in lymph nodes, sPLA2-IID mobilizes a pool of polyunsaturated fatty acids that can be metabolized to pro-resolving lipid mediators such as docosahexaenoic acid (DHA)-derived resolvin D1, which reduces Th1 cytokine production and DC activation. sPLA2-IID preferentially hydrolyzes phosphatidylethanolamine (PE) bearing DHA in lymph node membranes. This particular PE pool might reside into microvesicles, since sPLA2 acts on microvesicles shed from the cells at inflamed sites [18] and since leukocyte-derived microvesicles temporally generated in inflammatory exudates during resolution contain esterified biosynthetic precursors of pro-resolving mediators [19]. The fact that sPLA2-IID expression in DCs is downregulated after cell activation also accords with its anti-inflammatory role. Altogether, these results highlight sPLA2-IID as a “resolving sPLA2” that ameliorates inflammation through mobilizing DHA-derived proresolving lipid mediators (Fig. 2). This is the first demonstration of a particular sPLA2 that lies upstream of the pro-resolving lipid mediators in a tissue-specific context [17].

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4. Group V sPLA2, a “Th2/M2-prone sPLA2” that promotes Th2 immunity Currently, group V and X sPLA2s (sPLA2-V and sPLA2-X) have been implicated in the exacerbation of Th2-based asthma [20,21]. However, the mechanism of action of the two sPLA2s appears distinct. The phenotype of Pla2g10/ mice in the asthma model is rather confined to the airway, in which sPLA2-X is released from the airway epithelium and may act on infiltrating eosinophils to produce cysteinyl leukotrienes (cys-LTs) [20,22,23]. On the other hand, that of Pla2g5/ mice involves not only airway-resident cells, in which sPLA2-V may facilitate airway damage possibly via surfactant degradation [24], but also antigen-presenting cells, in which sPLA2V regulates antigen processing and thereby Th2 immune response [25]. In the latter, capture and processing of antigens by DCs are significantly attenuated in Pla2g5/ mice, which leads to reduced Th2 polarization and thereby inefficient propagation of asthma inflammation [23,26]. In contrast, Th2 immunity itself (e.g. IL-4 expression and IgE production) is not profoundly affected by Pla2g10 deficiency. Expression of sPLA2-V is markedly induced in T cells and macrophages by the signature Th2 cytokines IL-4 and IL-13, while it is downregulated by Th1 inducers such as interferon-g and Toll-like receptor agonists [26,27]. In a model of house dust mite-induced asthma, sPLA2-V expression in IL-4-driven M2 macrophages is sufficient for the development of pulmonary inflammation [26]. The levels of Th2-attracting chemokines and effector Th2 cell recruitment are severely impaired in the lung of Pla2g5/ mice. In the spleen, sPLA2-V is enriched in CD11c rather than CD11cþ phagocytic cells, further supporting its preferential distribution into M2-type macrophages [17]. Moreover, exogenous sPLA2-V facilitates M2 polarization of macrophages [27]. Thus, sPLA2-V is a unique sPLA2 that is induced by Th2 cytokines in Th2 cells and M2 macrophages and is involved in the promotion of a Th2 response by inducing M2 macrophages and by recruiting Th2 cells to amplify the effector phase of pulmonary inflammation. This property of sPLA2-V as a “Th2/M2-prone sPLA2” appears to be consistent with the fact that Pla2g5/ mice are protected from asthma

Fig. 2. sPLA2-IID resolves antigen-induced contact hypersensitivity through mobilizing pro-resolving lipid mediators. Application of hapten antigen (Ag) onto abdominal skin followed by the second application of the same antigen onto ear skin induced ear swelling. Skin DCs (Langerhans cells or dermal DCs) capture and process the Ag, migrate into the regional lymph nodes, and present it to T cells leading to Th1 polarization and propagation. sPLA2-IID, a “resolving sPLA2” that is preferentially and constitutively expressed in conventional CD4þCD11cþ DCs in the lymph nodes, hydrolyzes PE to supply DHA-derived pro-resolving lipid mediators such as resolvin D1 (RvD1), which can attenuate the Th1 immune response and thereby dermatitis [17].

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(Th2-dependent) [21], while they suffer from more severe arthritis (Th17-dependent) or infection (Th1-dependent) [28,29], where Th2 immunity counteracts Th1/Th17 immunity. Thus, this immune balance regulation by sPLA2-V could explain why this enzyme exhibits pro- or anti-inflammatory actions depending on distinct pathophysiological settings. This notion may also be true for the metabolic function of sPLA2-V, as described below. 5. Group V sPLA2, a “metabolic sPLA2” that counter-regulates obesity sPLA2-IB and -X have been proposed to act as “digestive sPLA2s” and to participate in body fat accumulation indirectly by controlling phospholipid digestion and absorption in the gastrointestinal tract [30,31]. However, the regulatory roles of sPLA2s in metabolic disorders including obesity and insulin resistance have not yet been fully elucidated. Although perturbation of lipoproteins by extracellular lipases variably and often profoundly affect obesity and insulin resistance [32], except for studies using sPLA2-overexpressing Tg mice [33,34], no reports have firmly established whether endogenous sPLA2s may affect lipoprotein metabolism in vivo. In a microarray search for unique lipase-related genes whose expressions are associated with obesity, it has recently been found that two particular sPLA2s (V and IIE) are robustly induced in adipocytes of obese mice and play distinct and previously unrecognized roles in diet-induced obesity through hydrolysis of lipoprotein phospholipids [27]. The obesity-driven induction of sPLA2-V in hypertrophic adipocytes, along with its constitutive expression at relatively high levels in the heart and skeletal muscle which have a high demand for lipids as an energy source [35], suggests that one of the primary roles of this sPLA2 may be related to the regulation of energy metabolism. Notably, when fed a high-fat diet, Pla2g5/ mice display hyperlipidemia with higher plasma levels of lipid-rich lowdensity lipoprotein (LDL), increased adiposity and fatty liver, reduced energy expenditure, increased plasma levels of leptin and insulin, and decreased insulin sensitivity [27]. sPLA2-V protects from metabolic disorders by normalizing phosphatidylcholine (PC) in fat-overladen LDL and by tipping the immune balance toward an

M2 state that counteracts adipose tissue inflammation. Mechanistically, unsaturated fatty acids (e.g. oleate and linoleate) released from hyperlipidemic LDL by sPLA2-V dampens M1 macrophage polarization by saturated fatty acids (e.g. palmitate), likely through attenuating endoplasmic reticulum stress. The induction of sPLA2V, a “metabolic sPLA2”, by fat-rich diet and its role in protection from accumulation of hyperlipidemic LDL [27] is compatible with that of sPLA2-IIA, an “inflammatory sPLA2”, by pro-inflammatory bacterial components (e.g. lipopolysaccharide) and its role in protection from bacterial infection [36] (Fig. 3). Given that adoptive transfer of bone marrow cells from Pla2g5/ mice attenuates plaque formation modestly in atherosclerosis-prone Ldlr/ mice [37], the pro-atherogenic function of sPLA2-V could be regarded as an adverse effect when LDL hydrolysis by hematopoietic sPLA2-V occurs in the local artery (see below). Moreover, considering the increased metabolic disorders observed after the genetic deletion of Th2 or M2 inducers (e.g. Il4, Il13, Il33, Stat6 or Pparg) [38], the reduced whole-body Th2/M2 status (see above) may also underlie the increased obesity in Pla2g5/ mice. Importantly, PLA2G5 mutations are associated with LDL levels in subjects with type 2 diabetes or obesity [39,40] and PLA2G5 expression in human visceral adipose tissue inversely correlates with LDL plasma levels [27], implying a human relevance of these findings. 6. Group IIE sPLA2, another “metabolic sPLA2” that facilitates fat accumulation Since the initial identification of group IIE sPLA2 (sPLA2-IIE) [15,41], the regulatory expression, specific substrates and functions of this sPLA2 have remained unknown for more than a decade. It has recently been shown that sPLA2-IIE acts as another “metabolic” sPLA2 that is induced in hypertrophic adipocytes. Pla2g2e/ mice are modestly resistant to diet-induced obesity, hepatic steatosis and hyperlipidemia [27]. In contrast to sPLA2-V that hydrolyzes PC in LDL and thereby protects from obesity-associated metabolic disorders (see above), sPLA2-IIE preferentially acts on minor lipoprotein phospholipids, phosphatidylserine (PS) and PE. sPLA2-IIE thus alters the lipid composition in lipoproteins, thereby moderately affecting fat deposition in adipose tissue and liver. Although

Fig. 3. Adipocyte-driven sPLA2-V acts as a metabolic regulator through hydrolysis of LDL phospholipids. sPLA2-V, a “metabolic sPLA2” that is induced in hypertrophic adipocytes following excess fat intake, protects from hyperlipidemia through hydrolytic normalization of fat-overloaded LDL. Unsaturated fatty acids such as oleic acid (OA) and linoleic acid (LA) released from LDL-PC by sPLA2-V suppresses M1 polarization of macrophages and ameliorates adipose tissue inflammation and obesity [27]. The proposed pro-atherogenic function of sPLA2-V [37] could be regarded as an adverse effect when LDL hydrolysis by hematopoietic sPLA2-V occurs in the local artery. This notion is compatible with the fact that sPLA2-IIA, an “inflammatory sPLA2” that is induced by pro-inflammatory stimuli, protects from infection by degrading PE and phosphatidylglycerol (PG) in bacterial membranes [36], while it exacerbates inflammation (e.g. arthritis) through hydrolyzing extracellular mitochondria as a DAMP [29,58].

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the molecular mechanism that links lipoprotein PS/PE hydrolysis with obesity remains to be elucidated, this study sheds light on the importance of these minor lipoprotein phospholipids in metabolic regulation and opens a future opportunity to analyze this issue using Pla2g2e/ mice as a novel tool. Unlike sPLA2-V, however, sPLA2-IIE is expressed at very low levels in human visceral adipose tissues, revealing a species difference. Collectively, these results underscore the physiological relevance of lipoprotein hydrolysis by distinct sPLA2s and highlights “metabolic sPLA2s” as integrated regulators of immune and metabolic responses [27]. Furthermore, this finding brings about a paradigm shift toward a better understanding of the biological roles of the sPLA2 family as a metabolic coordinator. 7. Complex roles of group X sPLA2 in atherosclerosis and diabetes Beyond the aforementioned metabolic regulation linked to LDL metabolism, sPLA2-mediated hydrolysis of LDL phospholipids is thought to be important for the promotion of atherosclerosis, as detailed in previous reviews [1e6]. In fact, atherosclerosis is accelerated in PLA2G2A-Tg or PLA2G3-Tg mice, in which potent hydrolytic modification of LDL occurs [33,34]. However, it remains obscure whether endogenous sPLA2s indeed exhibit proatherogenic actions in vivo, and if so, via hydrolysis and/or modification of LDL or not. Although adoptive transfer of Pla2g5/ bone marrow cells into Ldlr/ mice modestly reduces atherosclerosis development (as described above) [37], global Pla2g5/ mice on the Apoe/ background display few atherosclerotic symptoms, with only slightly reduced collagen deposition in the plaques [42], arguing against a major contribution of sPLA2-V to atherosclerosis. Varespladib, an sPLA2 inhibitor that broadly inhibits group I/II/V/X sPLA2s, shows some efficacies in preventing atherosclerosis in animal models [43], yet the phase III VISTA-16 clinical trial failed to prove a beneficial outcome of this compound in treating patients with cardiovascular diseases, and rather increases the risk of morbidity [44]. On the other hand, Ldlr/ mice reconstituted with bone marrow cells from Pla2g10/ mice unexpectedly display a doubling of plaque size compared with control mice [45]. Macrophages of Pla2g10/ mice are more susceptible to apoptosis, which is associated with an increase of plaque necrotic core. In addition, chimeric Pla2g10/ mice show exaggerated Th1 immune response in atherosclerotic plaques. Accordingly, adoptive transfer of PLA2G10-Tg bone marrow cells into Ldlr/ mice leads to the reduction of Th1 response and lesion size. Thus, sPLA2-X can be regarded as an “anti-atherogenic sPLA”2, whose hematopoietic expression attenuates the pro-atherogenic Th1 response and limits atherosclerosis development, yet the lipid metabolism responsible for the sPLA2-X action remains unclear in this setting. This result may provide an explanation for the failure of the VISTA-16 clinical study to treat patients with coronary artery diseases. As opposed to this finding, however, other reports have shown that Pla2g10/ mice have reduced atherosclerosis and aneurysm [46,47]. The opposite phenotypes might be due to different experimental models or housing conditions, and further studies will be necessary to depict more definitely the role and mechanism of action of sPLA2-X in atherosclerosis. The possible role of sPLA2-X in the regulation of metabolic disorders is also enigmatic, since there are controversial results [31,48,49]. The proposed mechanisms include the modification of LXR nuclear receptor signaling by polyunsaturated fatty acids released by sPLA2-X in the adrenal gland or adipose tissue or the regulation of dietary phospholipid digestion and absorption by sPLA2-X in the gut. Interestingly, a recent report has demonstrated

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a new role of sPLA2-X at controlling insulin secretion by islet b cells, where glucose-stimulated insulin secretion by islets is augmented in Pla2g10/ mice [50]. Mechanistically, sPLA2-X negatively regulates pancreatic insulin secretion by augmenting cyclooxygenase2-dependent PGE2 production. In this scenario, targeting sPLA2-X may be an effective therapeutic option in enhancing b cell function in the treatment of diabetes. 8. Group V and X sPLA2s in host defense It is well established that sPLA2-IIA acts as a “bactericidal sPLA2”, playing a role in host defense against invading bacteria (Grampositive in particular) by degrading the bacterial membrane [1e6]. Recent studies have shown that the lack of sPLA2-V or -X also influences pulmonary inflammation after infection with Gramnegative Escherichia coli and pandemic H1N1 influenza, respectively [51,52]. In a model of E. coli-induced pneumonia, Pla2g5/ mice have higher levels of E. coli in the bronchoalveolar lavage fluid and lung than Pla2g5þ/þ mice, and develop more severe respiratory acidosis and hypothermia, accompanied by a higher elevation of pulmonary pro-inflammatory cytokines, changes in eicosanoid levels, and a lower infiltration of immune cells [51]. These results suggest that sPLA2-V participates in the clearance of E. coli, reminiscent of its role in the phagocytic clearance of Candida albicans by macrophages [28]. Adoptive transfer reveals that the deletion of hematopoietic sPLA2-V impairs leukocyte accumulation, while its absence in either hematopoietic cells or non-hematopoietic cells (likely bronchial epithelial cells) attenuates E. coli clearance from the lung. As noted above, Pla2g10/ mice are protected from airway inflammation in a model of asthma [20], where epithelial-derived sPLA2-X promotes airway hypersensitivity by serving as an epithelial regulator of inflammatory eicosanoid formation [53]. In a distinct model of airway inflammation caused by H1N1 pandemic influenza infection, Pla2g10/ mice display a better survival than Pla2g10þ/þ mice, with lower production of eicosanoids (e.g. PGD2, PGE2, LTB4 and cysteinyl-LTs) and an earlier and more robust induction of T and B cell-associated genes [52]. Thus, activation of sPLA2-X during influenza infection is an early step of pulmonary inflammation and its inhibition increases adaptive immunity and improves survival. Hence, the selective inhibition of sPLA2-X may be an efficient strategy to treat airway inflammation caused by harmful antigens or influenza virus. 9. New aspects for the “old” group IB and IIA sPLA2s sPLA2-IB and -IIA are the two best known sPLA2s, originally purified from pancreas and platelets or synovial fluids, respectively, in the 80's. It is known that sPLA2-IB, after secretion from the pancreas into the intestinal lumen, plays a role in digestion of dietary and biliary phospholipids [1e6]. Perturbations of this event by genetic or pharmacological inhibition of sPLA2-IB protects from diet-induced obesity and hepatic steatosis due to reduced gut absorption of lipids [54], particularly lysophosphatidylcholine, which is a causal factor for hepatic insulin resistance and hyperlipidemia [55,56]. Besides, it has recently been reported that Pla2g1b/ mice on the Ldlr/ background are protected from atherosclerosis and body weight gain in response to a hypercaloric diet [57]. Thus, pharmacological inhibition of sPLA2-IB, a “digestive sPLA2”, may be a viable strategy to decrease diet-induced obesity and the risk of diabetes and atherosclerosis. sPLA2-IIA is often referred to as an “inflammatory sPLA2” or “bactericidal sPLA2” [1e6]. Although the ability of sPLA2-IIA to hydrolyze bacterial membranes and thereby kill bacteria has been

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well documented, the molecular mechanism underlying its proinflammatory action has remained incompletely understood. The first definitive evidence for an in vivo role of sPLA2-IIA in inflammation has been obtained in a mouse model of rheumatoid arthritis, in which PLA2G2A-Tg mice have an excerbated arthritis, while Pla2g2a/ mice have lower clinical signs of the disease [29]. More recently, it has been shown that extracellular mitochondria released from activated platelets (within membrane-encapsulated microparticles or as free organelles) serve as an endogenous substrate of sPLA2-IIA [58]. Hydrolysis of extracellular mitochondrial membrane by sPLA2-IIA yields pro-inflammatory lipid mediators and mitochondrial DNA, a kind of damage-associated molecular pattern (DAMP), which promote leukocyte activation. Thus, the identification of extracellular mitochondria, which have evolved from bacteria, as a physiological substrate of sPLA2-IIA, would provide an important mechanism to explain the pro-inflammatory action of this enzyme in many inflammatory disorders including rheumatoid arthritis. 10. New insights into the M-type sPLA2 receptor (PLA2R1) PLA2R1, which binds to several group I/II/V/X, but not group III and XII, sPLA2s with distinct affinities [59], is so far the best known sPLA2 binding protein [1,2]. PLA2R1 is an integral membrane receptor of 180 kDa, with a very large extracellular domain comprising 10 distinct domains and only a short cytoplasmic domain. PLA2R1 also exists as a soluble receptor produced by alternative splicing or shedding from the membrane-bound receptor. PLA2R1 may act in two opposite modes, either as a clearance receptor that inhibits, inactivates and removes sPLA2s from the extracellular milieu, or as a bona fide signaling receptor that transduces a sPLA2 cellular signal in a manner independent of the catalytic activity of sPLA2 [60]. PLA2R1 may also act as a pleiotropic receptor that functions by binding to non-sPLA2 ligands. Indeed, PLA2R1 is a paralog of macrophage mannose receptor and of two other similar receptors and belongs to the superfamily of C-type lectins, suggesting the presence of more ligands and functions beyond the sPLA2 [61]. For instance, PLA2R1 has been shown to be a potent regulator of cellular senescence and apoptosis in the context of aging and cancer [62,63] and also as the major autoantigen expressed in human podocytes and involved in membranous nephropathy, a severe human kidney autoimmune disease [64]. In 2013, a series of papers have reported novel in vivo roles of PLA2R1 using Pla2r1/ mice, which support all these possibilities [63,65,66]. In a model of allergen-induced asthma, Pla2r1/ mice display higher infiltration of eosinophils and neutrophils and higher levels of eicosanoids and Th2 cytokines in the airway [65]. Higher levels of sPLA2-IB and -X proteins, which are high affinity ligands for PLA2R1 [59], are also detected in the bronchoalveolar lavage fluid of Pla2r1/ mice compared to wild-type mice, providing the first in vivo evidence that PLA2R1 serves as a clearance receptor for these sPLA2s. In line with this finding, intratracheally-instilled sPLA2-IB is cleared and degraded more slowly in Pla2r1/ lung than wild-type lung. Given the pro-asthmatic roles of sPLA2-X and -V (see above), the exacerbated asthma phenotype in Pla2r1/ mice may be ascribed to the increased airway levels of sPLA2-X and possibly sPLA2-V, which has a weak affinity for the receptor [59]. Although sPLA2-IB is substantially expressed in the lung [65], its role in airway disease remains to be elucidated. In a model of myocardial infarction, PLA2R1 is primarily expressed in myofibroblasts in the infarcted region. Pla2r1/ mice exhibit higher rates of cardiac rupture than did wild-type mice after myocardial infarction [66]. Pla2r1/ mice show decreases in collagen content and a-smooth muscle actin-positive fibroblasts in

the infarcted region, and Pla2r1/ myofibroblasts are impaired in collagen-dependent migration, proliferation, and activation of focal adhesion kinase in response to sPLA2-IB. Binding of sPLA2-IB to PLA2R1 promotes migration and growth of myofibroblasts through functional interaction with integrin b1 and independently of its catalytic activity. Thus, PLA2R1 deficiency increases the susceptibility to post-infarction cardiac rupture through impaired healing of the infarcted region, which could be accounted for, at least in part, by the reduction of sPLA2-PLA2R1-coupled integrin signaling in myofibroblasts. However, as the cardiac expression of sPLA2-IB is very low, other sPLA2(s) or even non-sPLA2 component(s) may act as an endogenous ligand in this tissue. Alternatively, considering that the ablation of sPLA2-V or -X ameliorates myocardial infarction [67,68], the lower clearance of these offensive sPLA2s due to PLA2R1 deficiency might explain the observed phenotypes in Pla2r1/ mice. PLA2R1 may also function as a tumor suppressor, since its siRNA knockdown is sufficient to escape oncogene-induced senescence and thereby facilitates oncogenic cell transformation through the JAk2- or reactive oxygen species-dependent pathway [62,63,69]. Structure-function studies of PLA2R1 and the use of inhibitors for sPLA2-related signaling pathways suggest that the effect of PLA2R1 is sPLA2-independent. Notably, Pla2r1/ mice have increased sensitivity to carcinogen-induced skin tumorigenesis by facilitating senescence escape, further underscoring the physiological role of PLA2R1 as a tumor suppressor [62]. However, the facts that Pla2g2a-Tg mice display increased skin carcinogenesis [70], that group IIF sPLA2 (sPLA2-IIF) is abundantly expressed in skin [71] and that both sPLA2-IIA and -IIF are high affinity ligands for PLA2R1 [59], leave open the possibility that the protective effect of PLA2R1 on skin cancer is at least in part due to its role in the clearance of certain skin sPLA2s. Finally, PLA2R1 appears as a key protein expressed in human kidney, and more specifically in highly specific and differentiated epithelial cells called podocytes [64]. These cells are present within the glomeruli and play a major role in the glomerular filtration barrier, a highly specialized blood filtration interface. The physiological function of PLA2R1 in podocytes remains speculative, with PLA2R1 being either a component of the glomerular basement membrane that helps podocytes to adhere at the interface with blood capillaries or as a component of the slit diaphragm that constitutes the blood molecular sieving filter. Nonetheless, PLA2R1 was discovered as the major autoantigen in membranous nephropathy, a severe autoimmune disease leading to podocyte injury and high levels of proteinuria in patients [64]. In both of these contexts, it is not clear whether sPLA2s may play a role in the microenvironment of the glomerulus, either by circulating there from blood flow or after secretion from neighboring cells such as mesangial cells, which are for instance known to secrete sPLA2-IIA under inflammatory conditions [72]. Assessing the role of PLA2R1 in this system has currently been prevented by the absence of expression of PLA2R1 in podocytes from mouse kidney, another species difference. 11. Concluding remarks Classically, sPLA2s have been vaguely implicated in digestion, inflammation, host defense and atherosclerosis. Before the first edition of this Biochimie review series, only parts of the physiological functions in relation to this classical concept were assigned to the limited (“old”) members of sPLA2 (IB, IIA, V and X) [1,2]. Afterward, more diverse, non-redundant, and unexpected biological actions of individual sPLA2s have been clarified, which include the identification of (i) new functions for old sPLA2s, (ii) unique and unexpected biological roles for additional sPLA2 members (IID, IIE

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and III), and (iii) specific lipid pathways underlying the actions of these enzymes through sophisticated lipidomics techniques. Indeed, the discoveries of “anaphylactic (III)”, “resolving (IID)”, “Th2/M2-prone (V)”, “metabolic (V and IIE)”, and “anti-atherogenic (X)” sPLA2s and their target lipid pathways (substrates or products) have greatly expanded our understanding of sPLA2s, and we can now declare that a new era for sPLA2 has emerged. However, at the mechanistic level, it is still unclear in several situations whether sPLA2s act via their intrinsic catalytic activities, via cross-talk with intracellular PLA2s, or via non-enzymatic mechanisms including binding to PLA2R1 or other cellular components. Of note, the in vitro enzymatic properties of sPLA2s are very different from one to each other, both in terms of substrate specificity and turnover number, which would explain why the in vivo phenotypes observed in Tg mice overexpressing different sPLA2s are not identical [24,31,33,34,73,74]. We believe that even more sPLA2 functions will be deciphered throughout the analyses of sPLA2 knockout mice and studies of their molecular properties within the next decade. However, as most of our knowledge on sPLA2 functions has been obtained from mouse studies, it is important to translate these studies to humans with caution. Indeed, not all of these studies might be translated into humans, and even some sPLA2 functions, as described for sPLA2-V for instance [75], appear to depend on the mouse strain. The case of varespladib may be one example of such potential shortcoming between mouse and humans. Once the respective functions and mechanisms of action of sPLA2s will have been depicted in more details, some sPLA2s will more clearly appear as relevant drug targets or possibly as interesting bioactive and therapeutic molecules in several human diseases. In these cases, we will in turn need highly specific and potent inhibitors for each sPLA2 isoform, being able to block the offensive function of this particular sPLA2 in a specific tissue and under a particular disease condition, rather than using some pan-sPLA2 inhibitors like varespladib, which may have been futile at curing different human inflammatory diseases because they inhibit both offensive and defensive sPLA2s. Targeting specific sPLA2s and their organ expressions will be challenging, since these enzymes appear to play highly selective roles in specific organs and disease states.

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