Oxidized phospholipid signaling: Distress to eustress

CHAPTER

Oxidized phospholipid signaling: Distress to eustress

15 Corinne M. Spickett

Department of Biosciences, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom

Abstract In addition to direct oxidation of proteins by hydrogen peroxide or superoxide, the formation of reactive lipid electrophiles through the process of lipid peroxidation allows an indirect form of signaling, as reactive lipid oxidation products are recognized by a variety of receptors and moreover can form adducts with proteins, thus altering their function. Thus, oxidized lipid products can be perceived as secondary signals. Owing to the wide variety of products of phospholipid oxidation, the biological effects on cells and signaling pathways affected are very diverse. While many proinflammatory effects are considered detrimental and are thought to contribute to disease pathology, a number of anti-inflammatory and protective effects involving antioxidant upregulation are also known. Reactivity of the oxidized lipid products, in terms of their ability to form adducts with proteins, is an important determinant of many of the cellular responses. The catalogue of cellular targets of oxidized lipid products is constantly expanding and partially overlaps with the targets of more direct redox signaling induced by hydrogen peroxide. ­Keywords: Phospholipid oxidation, Lipoxidation, Electrophilic ­4-Hydroxynonenal, Receptor interactions, Adaptive response

oxidized

lipids,

­Introduction to redox signaling concepts There has been a revolution in thinking about the concept of oxidative stress, with recognition that free radicals (e.g., superoxide) and partially reduced oxygen species (e.g., hydrogen peroxide) can have beneficial signaling functions that regulate physiological processes (Forman, 2016; Sies, 2014). This can vary from signal transduction in response to growth factors, resulting in proliferation or differentiation, to responses to external stresses that enable the cell or organism to adapt to and survive in adverse conditions (Egea, Fabregat, Frapart, et al., 2017). The most widely understood mechanisms involved in these responses are the oxidation of regulatory proteins, which usually involve reversible oxidation of susceptible cysteine residues to disulfides. These residues, as well as lysines and histidines, can also be modified covalently by reactive lipid oxidation products, which are formed under conditions of Oxidative Stress. https://doi.org/10.1016/B978-0-12-818606-0.00015-8 © 2020 Elsevier Inc. All rights reserved.

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altered redox balance and oxidative stress. Unsaturated phospholipids are susceptible to hydrogen abstraction by the highly reactive species hydroxyl radical and subsequent peroxidation in the presence of O2 (Catala, 2009; Gueraud, Atalay, Bresgen, et al., 2010; Reis & Spickett, 2012) (Niki, this book). Production of hydroxyl radicals from hydrogen peroxide is catalyzed by ferrous ion (Fe2+) via the Fenton reaction, and other transition metals with multiple oxidation states can also support analogous reactions. UV exposure of lipids also leads to similar reactions and is very relevant to UV-mediated damage to skin (Gruber, Oskolkova, Leitner, et  al., 2007). Many of the products of adventitious oxidation are similar to enzymatic products of fatty acid oxidation, which known as immunomodulatory signaling molecules; these include prostaglandins, thromboxanes, leukotrienes, resolvins, and maresins (Bennett & Gilroy, 2016; Serhan & Levy, 2018; Tang, Wan, Huang, et al., 2018). Furthermore, since the 1990s, evidence has been accumulating to support the concept that fatty acid oxidation products esterified within phospholipids also have a variety of biological effects of both proinflammatory and anti-inflammatory nature (Bochkov, Oskolkova, Birukov, et al., 2010; Greig, Kennedy, & Spickett, 2012). Thus, products of phospholipid oxidization can be considered as secondary or indirect signals of oxidative stress. This chapter will explore current understanding of the diverse biological effects exerted by oxidized phospholipids and their breakdown products, and consider the factors that influence the balance between deleterious stress and beneficial eustress.

­Oxidized phospholipids and their products The oxidation of lipids can occur by enzymatic or nonenzymatic processes. The enzymatic pathways use mainly nonesterified fatty acids as substrates, while adventitious oxidation more commonly involves attack on phospholipids, as these are abundant in cell membranes and lipoproteins. The enzymatic pathways are stereospecific and yield a more limited (though analogous) panel of products, in contrast to the nonenzymatic process (O’Donnell & Murphy, 2012). This produces a plethora of racemic species, as the primary products are relatively unstable and can readily be converted to other products by further oxidation, rearrangement of the hydroperoxide(s) including cyclization reactions or radical cleavage, or reduction of the hydroperoxides to hydroxides. For example, the well-known products isoprostanes are formed by further oxidation and endocyclization, and the highly reactive isolevuglandin family is formed by a similar pathway (Davies & Guo, 2014; Dixon, Davies, & Kirabo, 2017). Nitrogen-containing radicals (e.g., nitrogen dioxide) derived from peroxynitrite can also react with unsaturated fatty acyl chains, as can hypohalites such as HOCl. The result is a plethora of products containing functional moieties such as hydroxides, ketones, epoxides, chloro, nitro and nitroso groups, cyclopentanones or cyclopentenones within the chain, and aldehyde or carboxylic ω-terminal groups, which have been described in detail (Spickett & Pitt, 2015; Spickett, Wiswedel, Siems, et al., 2010).

­Oxidized phospholipids and their products

Lipid oxidation products can be divided into a number of categories depending on characteristics that influence their biological signaling effects; essentially, these are ­full-chain length oxidized phospholipids usually at the sn2 position, phospholipids containing a truncated fatty acyl chain, and nonesterified breakdown products, which are formed from the cleavage reactions that generate the truncated chain lipids (Fig. 1). Each of these categories can be further subdivided in terms of reactivity, in particular their ability to react with nucleophilic groups on other macromolecules such as proteins, leading to adduct formation (lipoxidation). Lipid oxidation products containing aldehydes (alkanals) are able to react with amines to form Schiff bases; the reactivity is increased in 2-alkenals (α,β-unsaturated species) where the double bonds are conjugated, especially if γ-substitution is present, as in 4-hydroxyalkenals such as 4-hydroxynonenal (HNE). The carbon at position 3 is particularly susceptible to nucleophilic attack by primary or secondary amines and thiols, leading to the formation of Michael adducts, as reviewed recently (Parvez, Long, Poganik, et  al., 2018; Sousa, Pitt, & Spickett, 2017). Analogous chemical structures in other lipid oxidation products also form Michael adducts, such as cyclized species containing a substituted cyclopentenone ring, for example, in deoxy-prostaglandin J2 (Domingues, Domingues, Melo, et al., 2013). While most early work focused on adduct formation by the short-chain reactive aldehydes (especially acrolein, malondialdehyde, and HNE), later research included both nonesterified and esterified reactive lipid species (Aldini, Domingues, Spickett, et al., 2015; Spickett, Reis, & Pitt, 2013). Phospholipids containing nucleophilic moieties in their polar head groups (phosphatidylserine and phosphatidylethanolamine) can also be covalently modified (Annibal, Schubert, Wagner, et al., 2014; Davies & Guo, 2014).

FIG. 1 Categorization of lipid oxidation products according to their structural and chemical properties. Structures are divided according to whether they are esterified, full chain length, or fragmented, while chemical properties relate to their reactivity with other biomolecules and propensity to form adducts with proteins.

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An ongoing challenge is the elucidation of the biological effects of different oxidized phospholipid products and the mechanisms underlying these effects. Understanding of the signaling pathways is further complicated as it appears that protein adducts of oxidized phospholipids may retain some properties of the original oxPLs (van Der Valk, Bekkering, Kroon, et al., 2016).

­Oxidized lipid signaling versus damage Traditionally, the enzymatic pathways of lipid peroxidation, involving enzymes such as cyclooxygenases, lipoxygenases, and cytochrome P450-dependent enzymes, were viewed as physiological processes involved in cell signaling and immune regulation. The major products known originally were eicosanoids, formed from arachidonic acid by addition of oxygen and subsequent rearrangements to produce several families of structurally related C20 molecules, all in nonesterified form (Bennett & Gilroy, 2016). In contrast, the nonenzymatic oxidation products were viewed as simply as accidental damage and therefore undesirable outcomes of inflammation or other conditions involving oxidative stress (distress), leading to membrane damage and cell death (O’Donnell, Aldrovandi, Murphy, et al., 2019). Oxidized phospholipids are known to disrupt the phospholipid bilayer through altered polarity of the fatty acyl chains and steric effects (Megli, Russo, & Conte, 2009); the lipid whisker hypothesis proposes that the oxidatively modified fatty acyl chains become de-embedded and protrude into the extramembrane space, which facilitates their interactions with other molecules (Greenberg, Li, Gugiu, et al., 2008). However, many of the products of phospholipid peroxidation are esterified analogues of free enzymatic products, apart from the key difference that they lack stereospecificity. Some lipoxygenases can catalyze the oxidation of membrane phospholipids; human 15-LOX-1 and murine leukocyte-type 12-LOX accept phospholipids as substrates (O’Donnell et al., 2019). Nonenzymatically formed oxidized phospholipids exert a wide variety of biological effects that do not simply mimic those of the nonesterified oxidized fatty acids. Moreover, as well as oxPLs having proinflammatory actions that are thought to contribute to pathology in a variety of inflammatory diseases, it is clear that they can have anti-inflammatory actions and stimulate protective responses such as antioxidant production (Bochkov et al., 2010; Bochkov, Gesslbauer, Mauerhofer, et al., 2017; Greig et al., 2012; Karki & Birukov, 2018). Thus, the biological effects of enzymatically and chemically oxidized PLs have significant overlap and may be functionally linked during chronic inflammation (O’Donnell et al., 2019). An alternative concept is that reactive breakdown products of lipid peroxidation, such as HNE, can also induce signaling processes leading to beneficial cellular responses (Forman, 2010). Thus, it is essential to unravel potentially physiological and hormetic actions (eustress) from purely damage-related deleterious effects (distress).

Overview of signaling mechanisms for lipid oxidation products

­ verview of signaling mechanisms for lipid oxidation O products: Noncovalent versus covalent interactions At the most basic level, distress can be interpreted as purely physical damage leading to an irreversible loss of function, in contrast to eustress, which requires biochemical interactions that alter signaling pathways and cell behavior, with a potentially beneficial outcome. While this may be an oversimplification, nevertheless, the concept of signaling brings several requirements (Forman, Ursini, & Maiorino, 2014). For example, signaling tends to be understood as a process of one or more switches that change reversibly the function of a pathway leading to a cellular outcome, which might be a metabolic alteration or change in gene expression. This commonly depends on specific noncovalent ligand interactions with a receptor, which then transduces the effect. Consequently, there has been considerable effort to identify receptors that can bind oxidized lipids and the downstream pathways affected, with a fair amount of success. Oxidation of the fatty acyl chain (or, in some cases, modification of the head group) alters the chemical structure, increasing the polarity and changing the topography of the ligand to allow selective recognition compared with the native lipid (Bochkov et al., 2017). Some examples of this mechanism include the recognition of truncated oxPLs by the PAF receptor and the interaction of oxPLs with PPARs, scavenger receptors, or Toll-like receptors (Fig. 2). Noncovalent ligand interactions with cellular receptors can be considered as physiological or pathophysiological signaling, although in some cases the outcomes may have deleterious effects, such as inflammation or triggering of apoptosis. An alternative signaling mechanism relies on covalent modification of a protein that alters its activity, interactions with other proteins, or cellular location. Oxidized lipid products containing electrophilic elements (aldehydes, α,β-unsaturated alkenals, and cyclopentenone rings) are able to form covalent adducts with nucleophilic residues of proteins and thus have the potential to modulate signaling. On the other hand, the formation of covalent lipoxidation adducts on other proteins may result in a loss of function, as has been noted for the effects on a variety of enzymes and proteins (Domingues et  al., 2013; Sousa, Ahmed, Dann, et  al., 2019), which therefore could be considered as systemic distress. Moreover, there is a growing area of adaptive immunity that considers oxidized lipid products as damage-associated molecular patterns and neoantigens (Binder, Papac-Milicevic, & Witztum, 2016). While it is possible that some membranelocated oxidized phospholipids may themselves be recognized, it is more likely that the “oxidation-specific epitopes” result from covalent modifications of cell surface or extracellular proteins, especially in view of the fact that highly reactive products are very effective (Dixon et al., 2017). While this is in line with the concept of cellular damage, it also falls into the category of regulation of immune responses. The effects of oxidized phospholipids and their downstream products involve all these types of signaling pathways (Fig. 2).

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FIG. 2 Common modes of signaling by oxidized lipid products. (A) oxPL products bind to cell surface receptors, which transduce the interaction via various signaling pathways to upregulate gene expression. (B) oxPL products prevent binding of the normal ligand to cell surface receptors, inhibiting the normal signal transduction pathway. (C) oxPL products diffuse through the cell membrane and bind to intracellular receptors, which then act as transcription factors to upregulate gene expression. (D) oxPL products diffuse through the cell membrane and covalently modify signaling proteins, causing degradation of the inhibitor and release of the transcription factor.

­Examples of the biological effects of oxidized lipids products

E­ xamples of the biological effects of oxidized lipids products ­Studies of oxPL mixtures Following the discovery by Judith Berliner’s group in the 1990s that air-oxidized 1-palmitoyl-2-arachidonyl-3-glycerophosphocholine (oxPAPC) mimicked the proatherogenic effects of oxidized low-density lipoprotein by stimulating leukocyteendothelial cell adhesion (Watson, Leitinger, Navab, et al., 1997), there has been extensive research using oxPAPC as a model to investigate oxidized phospholipid effects. In addition to the demonstration of leukocyte-endothelial cell adhesion, other proinflammatory effects of oxPAPC have been reported. These include the induction of cytokines (e.g., IL-8, MCP-1, IL-6, MIP-1α, and β) (Furnkranz, Schober, Bochkov, et al., 2005; Gargalovic, Gharavi, Clark, et al., 2006; Lee, Shi, Tontonoz, et al., 2000), modulation of NADPH oxidase activity (Bluml, Rosc, Lorincz, et al., 2008; Lee, Gharavi, Honda, et  al., 2009), smooth muscle cell differentiation and migration (Cherepanova, Pidkovka, Sarmento, et al., 2009; Pidkovka, Cherepanova, Yoshida, et al., 2007), macrophage polarization (Serbulea, Deweese, & Leitinger, 2017), and promotion of foam cell formation through binding to scavenger receptors such as LOX and CD36 (Gao, Sayre, & Podrez, 2015; Silverstein, Li, Park, et al., 2010). In a drive to understand the mechanisms involved, evidence has been found for interactions with a number of additional receptors, such as platelet and neutrophil PAF receptors, PPARα, PKA, CD14, and Toll-like receptors (TLRs) (Cole, Subbanagounder, Mukhopadhyay, et al., 2003; Erridge, Kennedy, Spickett, et al., 2008; Latchoumycandane, Nagy, & McIntyre, 2015; Lee et al., 2000). The latter family has proved controversial, with some studies providing evidence of interactions (Kadl, Sharma, Chen, et al., 2011; Serbulea, Upchurch, Ahern, et al., 2018; Walton, Hsieh, Gharavi, et al., 2003), while others reported a lack of stimulation by oxPAPC (Erridge, Webb, & Spickett, 2007), and it further became clear that oxPLs could antagonize the activation of TLRs 2 and 4 by a variety of pathogenassociated molecular patterns (PAMPs) (Bochkov, Kadl, Huber, et al., 2002; Erridge et al., 2008; Walton, Cole, Yeh, et al., 2003). This effect can be considered as an ­anti-inflammatory response, and data on more beneficial effects of oxPLs are now increasing, such as inhibition of T cell proliferation and Th1 responses (Seyerl, Bluml, Kirchberger, et  al., 2008), modulation of dendritic cell function (Bluml, Zupkovitz, Kirchberger, et  al., 2009; Bretscher, Egger, Shamshiev, et  al., 2015), and barrier-protective effects in lung endothelial cells (Birukov, Bochkov, Birukova, et al., 2004; Birukova, Starosta, Tian, et al., 2013; Karki & Birukov, 2018). Similarly to the findings using nonesterified fatty acid oxidation products (see Niki, this book), oxPAPC has been found to cause the upregulation of antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), and glutamate-cysteine ligase (GCL) in endothelial cells and fibroblasts (Gruber et al., 2007; Jyrkkanen, Kansanen, Inkala, et al., 2008). These effects tend to be dependent on signaling through the Nrf-2-KEAP-1 system (Patinen, Adinolfi, Cortes, et al., 2019; Sihvola & Levonen, 2017). Interestingly, expression array analysis of

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genes induced by oxPAPC has shown endoplasmic reticulum stress, and genes related to the unfolded protein response (UPR) are strongly upregulated (Gargalovic et al., 2006). This is probably linked to covalent adduct formation and cross-linking reactions, especially as some electrophilic lipid species are known to cause proteasomal inhibition (Hohn, Jung, & Grune, 2014). Few studies have investigated other phospholipids such as oxidized phosphatidylethanolamine, phosphatidylserine, and cardiolipin. Early work on oxPLs suggested that the oxidation of the fatty acyl chains was more important than the phospholipid head group (Subbanagounder, Leitinger, Schwenke, et al., 2000), but it is also known that oxidized phosphatidylserine is externalized on apoptotic cells and leads to their recognition by CD36 on macrophages (Greenberg, Sun, Zhang, et al., 2006; Kagan, Borisenko, Serinkan, et al., 2003); similar findings have been reported for oxidized phosphatidylethanolamine (Uderhardt, Herrmann, Oskolkova, et al., 2012). Oxidation of mitochondrial cardiolipin can be catalyzed by the peroxidase activity of cytochrome c and is a mechanism in apoptosis (Kagan, Bayir, Belikova, et al., 2009). The use of oxPAPC, or analogous oxPL mixtures, have the advantage they are easily prepared in-house, which is important as only a small number of oxidized phospholipid species are commercially available. However, oxPAPC is a mixture of several dozen full-chain and truncated oxidized phospholipids and the corresponding chain fragments, as has been described previously (Bochkov et al., 2010; Spickett, Reis, & Pitt, 2011; Watson et al., 1997), so the use of such mixtures does not allow the effects of specific oxPLs or secondary products to be elucidated and limits the conclusions that can be drawn from these experiments, as potentially interfering species may be present. This may have contributed to conflicting reports in the early literature over the effects of oxPL mixtures; indeed, recent work has shown that preparations of oxPAPC produced in different laboratories yield distinct oxidized lipid profiles, in particular with different ratios of truncated to full-chain products (Ni et al., 2019).

­Effects of individual oxidized lipids or oxidized lipid families It is important to determine the effects of a variety of different oxPL products to understand the overall contributions to cell behavior. Data on the effects on individual oxPL species are accumulating and suggest that some effects that involve modes of signaling are specific to particular lipid oxidation product types. Table 1 shows examples of the diverse biological effects organized according to the type of oxidized phospholipid product. Some effects, such as the stimulation of monocyte-endothelial cell adhesion and inhibition of LPS-induced TLR4 activation in endothelial cells, appear to be induced by all types of esterified oxidized phospholipids regardless of whether they are truncated or reactive (Freigang, 2016). For other biological effects, differences emerge. On the whole, fragmented oxidized phospholipids tended to have effects that can be more regarded as distress, such as inducing or mediating apoptosis, inducing the release of inflammatory cytokines and oxidative burst, and disrupting endothelial barrier properties in the lung vasculature. In contrast, for f­ull-chain oxidized phospholipids, whether containing reactive moieties or not, g­ enerally, more

Table 1  Overview of typical effects of individual phospholipid oxidation products or families of products in cultured cells. Oxidized lipid species

Biological response observed

Type of effect

Reference

Proinflammatory (distress)

Yeon, Yang, Lee, et al. (2017)

Cytotoxicity (distress)

Seimon, Nadolski, Liao, et al. (2010)

Kim, Choi, Koo, et al. (2013), Meliton, Meng, Tian, et al. (2015), von Schlieffen, Oskolkova, Schabbauer, et al. (2009) Latchoumycandane, Marathe, Zhang, et al. (2012)

Fragmented reactive oxPL species

KOdiAPC and POVPC

Stimulated activation of procaspase-1 and generation of mature IL-1β and IL-18 in mouse macrophages Promote the apoptosis of macrophage-foam cells by activating TLR2 and CD36

Fragmented nonreactive oxPL species PGPC, PAzPC, PAPC-OH

Inhibited the effects of LPS and peptidoglycan

Anti-inflammatory

PAzPC

Required in TNF-α induced apoptosis of Jurkat cells; effect suppressed by GPx4

Anti-inflammatory/toxicity

Any fragmented oxPL species POVPC and PGPC

POVPC, PGPC

POVPC, PGPC, lyso-PC

Inhibited phagocytosis by alveolar macrophages and bacterial clearance in vivo Activated PPARα in endothelial cells, although this also stimulated basal production of IL-8 and MCP-1 The lung endothelial barrierdisruptive at all concentrations

Antiresolving (distress)

Thimmulappa, Gang, Kim, et al. (2012)

Partially anti-inflammatory

Lee et al. (2000)

Proinflammatory (distress)

Birukova et al. (2013)

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Continued

­Examples of the biological effects of oxidized lipids products

POVPC

272

Oxidized lipid species POVPC or PGPC

POVPC and PGPC

POVPC, PGPC or KOdiAPC

Butanoyl-PAF, butenoylPAF, POVPC

Biological response observed Did not interfere with the presentation of mycobacterial antigens to T cells Did not induce expression of proinflammatory genes via TLR2 in murine macrophages Did not inhibit the proinflammatory cytokine responses in TLR-activated dendritic cells [40] Stimulates neutrophil adhesion, lysosomal enzyme release, and oxidative burst via PAF receptor agonist activity

Type of effect

Reference

Negative

Cruz, Watson, Miller, et al. (2008)

Negative

Kadl et al. (2011)

Negative

Bretscher et al. (2015)

Proinflammatory (distress)

Smiley, Stremler, Prescott, et al. (1991)

Anti-inflammatory

Bretscher et al. (2015)

Anti-inflammatory

Cruz et al. (2008)

Full-chain length oxPL species (all) PEIPC and PECPC

PEIPC

Inhibited secretion of IL-6 and IL-12 in TLR-activated dendritic cells and inhibited their induction of T cells to a proinflammatory Th1 subset Inhibited secretion of TNFα and modulated TLR2-induced IL-12 and IL-10 production in mycobacterial infection

CHAPTER 15  Oxidized phospholipid signaling: Distress to eustress

Table 1  Overview of typical effects of individual phospholipid oxidation products or families of products in cultured cells—cont’d

PEICP

PEIPC

Isolevuglandins

Anti-inflammatory

Cruz et al. (2008)

Anti-inflammatory and protective Antioxidant-induction (eustress)

Birukov et al. (2004), Birukova et al. (2013) Jyrkkanen et al. (2008), Li, Chen, Yanes, et al. (2007)

Proinflammatory (distress)

Dixon et al. (2017)

Protective response: antioxidant induction (eustress)

Reviewed by Freeman, O’Donnell, and Schopfer (2018), Patinen et al. (2019), Sihvola and Levonen (2017)

Protective response

Jacobs and Marnett (2010)

Anti-inflammatory (eustress)

Cernuda-Morollon, Pineda-Molina, Canada, et al. (2001)

Nonesterified reactive species Aldehydes (4-HNE), CyPGs (PGA2, 15d-and PGJ2), nitroalkenes HNE 15d-PGJ2

Activate Nrf2, although C151 in KEAP1 is not the primary target for nitro-fatty acids and cyPGs Activate heat-shock responses via HSF1 Blocked NFκB-dependent inflammatory responses by inactivating IKKβ via cysteine binding

Continued

­Examples of the biological effects of oxidized lipids products

PEIPC

Interfered with the presentation of mycobacterial antigens to T cells [20] Improved lung endothelial barrier-protective action Induces Phase II responses via NRF2 in a thiol-dependent manner, including expression of OKL38 oxidative stress response gene Modify proteins to generate neoantigens and activate dendritic cells

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Oxidized lipid species Hydroxyalkenals (HNE and HDDE)

HNE

HNE, acrolein

HNE

HNE

Biological response observed Activate PPARδ in beta cells and vascular endothelial cells leading to adaptation to high glucose (insulin secretion) Reduced myeloid-endothelial cell adhesion by modification of α-enolase to reduce its binding to plasminogen Induced apoptosis by activating caspase-3, via modification of cysteine residues Breast cancer cell cytotoxicity by activation of peptidyl-prolyl cis/trans-isomerase A1 (Pin1) causing toxicity Activate JNK MAPK pathway to induce stress responses and modulate differentiation, motility, and apoptosis

Type of effect

Reference

Protective response (eustress)

Reviewed by Cohen, Riahi, Sunda, et al. (2013), Sasson (2017)

Anti-inflammatory and antitumor

Gentile, Pizzimenti, Arcaro, et al. (2009)

Toxicity (distress)

Finkelstein, Ruben, Koot, et al. (2005)

Toxicity (distress)

Aluise, Rose, Boiani, et al. (2013)

Not specified

Parola, Robino, Marra, et al. (1998), Uchida, Shiraishi, Naito, et al. (1999)

CHAPTER 15  Oxidized phospholipid signaling: Distress to eustress

Table 1  Overview of typical effects of individual phospholipid oxidation products or families of products in cultured cells—cont’d

­Examples of the biological effects of oxidized lipids products

anti-inflammatory or beneficial effects were reported, including protection of the lung endothelial barrier and interference with proinflammatory signaling pathways (Karki & Birukov, 2018; Mauerhofer, Philippova, Oskolkova, et al., 2016). Interestingly, reactive and electrophilic lipid oxidation products that are able to form adducts and might therefore be considered as damaging actually had many beneficial actions. The main common mechanism underlying this is their ability to react with cysteine residues in KEAP1 to induce release of Nrf2 and induction of Phase 2 response genes that lead to cellular protection through the upregulation of antioxidant and other defenses (Patinen et  al., 2019). This has been shown to be induced by a wide variety of α,β-unsaturated-, hydroxyalkenal-, and cyclopentenone ­ring-containing species, including PEIPC, PGJ2, HNE, and nitro-fatty acids (Freeman et  al., 2018; Jyrkkanen et  al., 2008; Li et  al., 2007). Less well known is the ability to induce a heat-shock response, which also results in increased cellular resistance to stresses; this has been reported for HNE, and adducts with HSF1 may be instrumental in the mechanism (Jacobs & Marnett, 2010). A wide variety of protein targets of electrophilic species have been reported and reviewed previously (Gueraud, 2017; Oeste & PerezSala, 2014; Parvez et al., 2018), which have mostly been identified by the use of liquid chromatography-mass spectrometry approaches to detect the site of adduct formation. Some of these cellular targets are illustrated in Fig. 3. While for most proteins covalent

FIG. 3 Commonly reported targets of oxidized lipid product signaling. The oxidized lipid products involved are shown in red and hydrogen peroxide signaling targets in blue. Note that this is not an exhaustive list; readers are referred to references in Table 1 for further details.

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modification leads to a loss of function through inactivation of catalytic residues, conformational changes, or aggregation, in a few cases, an activation has been observed. Notable examples include caspase-3 and H-ras; the latter may be due to subcellular redistribution following lipoxidation (Oeste, Diez-Dacal, Bray, et al., 2011). On the other hand, despite their reactivity, certain hydroxyalkenals have signaling effects that are normally induced by noncovalent ligand receptor interactions, such as the observation that 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) and 4-HNE activate PPARδ in vascular endothelial cells and insulin-secreting beta cells, leading to adaptation to hyperglycemic conditions (Cohen et al., 2013). POVPC was also noted to activate PPARα in endothelial cells (Lee et al., 2000). However, it is also possible that covalent binding does occur in these situations but does not interfere with the downstream signaling process (Sasson, 2017).

­Eustress versus distress: A matter of concentration? As with all signaling processes, the effects described earlier are concentration dependent, although in many cases the exact concentration ranges have not been elucidated. However, there is growing evidence for differential effects. (Subbanagounder, Wong, Lee, et  al., 2002) reported that lower oxPL concentrations inhibited LPS-induced E-selectin expression than were required to elicit proinflammatory cytokine secretion from endothelial cells in vitro. A wide variety of oxPL mixtures (oxPAPC, o­ xPLPC, oxPDHPC, oxPAPS, oxPAPG, and oxPAPA) and several individual species (PEIPC, POVPC, PGPC, and PAPC-OOH) were tested for their relative ability to inhibit LPSinduced IL-8 or E-selectin expression versus inducing inflammatory responses in the absence of a PAMP (Oskolkova, Afonyushkin, Preinerstorfer, et  al., 2010). While the exact concentrations required for inhibition versus activation of inflammatory responses varied between the oxidized phospholipids tested, in most cases, concentrations of 2–20 μM showed robust inhibition of LPS-induced effects, whereas concentrations above 50 μM were required for oxPL-induced production of inflammatory mediators, with 100 μM often yielding maximal response. Similarly, while oxPAPC at concentrations of 5–25 μg/mL (approximately 6–30 μM) increased lung endothelial cell resistance and barrier function, at concentrations above 50 μg/mL, barrierdisruptive effects were noted (Birukova et al., 2013). Cytotoxicity also tend to require concentrations of 50 μM or higher, although this may depend on many factors such as cell type, levels of detoxifying enzymes, treatment time, and cell-treatment ratio. Apoptosis of HL60 cells was observed at about 5 μM concentration of the synthetic ether lipid O-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocholine but was suppressed by overexpression of PAF acetylhydroxylase (Chen, Yang, & McIntyre, 2007). The concentrations given earlier were those present in the medium; as oxPLs can bind to or react with proteins in the medium, the levels within the treated cell may be substantially lower. Data on the levels of oxPLs in  vivo show a range of tissue or plasma concentrations, and comparison is hampered by the different measures used (e.g., μg/g wet tissue, % of total PC, and ng/mg of PAPC) (Bochkov et  al., 2010;

Oxidized lipid signaling

Greig et al., 2012). The highest levels reported were for POVPC, PGPC, and PEIPC in atherosclerotic rabbit aorta (40–100 μg/g wet tissue). The levels of other oxPLs such as HOOA, KOOA, KOdiAPC, and PAzPc in diseased aorta were much lower (1–10 μg/g wet tissue), while levels in plasma were more commonly 0.1–5 μM at most. The effects of many nonesterified electrophilic lipid products also follow a biphasic trend. Bauer and Zarkovic report that 4-HNE at 1–2 μM and higher directly inactivated membrane-associated catalase of tumor cells, whereas at submicromolar concentrations, 4-HNE triggered a complex pathway dependent on hydrogen peroxide and peroxynitrite interaction (Bauer & Zarkovic, 2015). A complex dose dependence is expected for electrophilic lipid oxidation products, where low levels may target only reactive sites in specific proteins, such as catalytic or regulatory cysteine residues with low pKa, while high concentrations lead to more extensive and nonspecific protein modification, causing conformational changes, protein unfolding, and cross-linking. This concept is well established for proteasomal protein degradation, where low levels of oxidation or modification by α,β-unsaturated compounds increased the rate of protein degradation, but high stress levels result in protein crosslinking and the formation of protein aggregates that inhibit proteasomal function (Ferrington & Kapphahn, 2004; Jung, Hohn, & Grune, 2014). Free HNE is present at levels of 0.2–0.7 μM in plasma, but ~10-fold higher concentrations have been reported in monocytes; concentrations of 10–50 μM are considered to be pathological (Zhang & Forman, 2017).

­ xidized lipid signaling: Parallels with hydrogen O peroxide-based redox signaling Signaling by oxidized lipid products can occur due to noncovalent receptor-ligand interactions or covalent modification of a cellular protein (lipoxidation), causing altered activity. The cellular outcomes of this signaling are extremely diverse and are concentration dependent, with lower levels inducing signaling effects that can often be considered as beneficial “eustress,” while higher levels have more damaging outcomes that can be classified as distress to the system. It is counterintuitive that the reactive lipid oxidation products that cause lipoxidation, at least under certain conditions, tend to upregulate cellular defenses, thus likely falling into the eustress category. On the other hand, these reactive compounds can also generate neoantigens and potentially contribute to autoimmune diseases (Binder et al., 2016). Moreover, outcomes in biology are often multifaceted; for example, oxidized lipid products can induce apoptosis, which may be bad for plaque stability if smooth muscle cells are the targets but beneficial if tumor cells or autoreactive T cells are involved. Interestingly, 4-HNE is now one of the most studied lipid oxidation products and has been described as a “second messenger of free radicals” (Zarkovic, 2003), on the basis that radical reactions are required to initiate lipid peroxidation. 4-HNE and other oxidized phospholipid products of similar chemical characteristics target an extensive panel of cellular proteins (Aldini et al., 2015; Davies & May-Zhang, 2018;

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Gueraud, 2017; Jacobs & Marnett, 2010; Oeste & Perez-Sala, 2014; Parvez et al., 2018; Perez-Sala, 2014). Often, the residues susceptible to adduction are thiol residues of low pKa, which in some cases are similar to those involved in oxidation and signaling by hydrogen peroxide. The signaling pathways redox-regulated by H2O2 include MAP kinases, protein tyrosine phosphatases, PTEN, NFκB, KEAP1-Nrf2, and caspases (Di Marzo, Chisci, & Giovannoni, 2018; Egea et al., 2017; Forman, 2016; Forman et al., 2014; Lennicke, Rahn, Lichtenfels, et al., 2015; Marinho, Real, Cyrne, et al., 2014; Spickett, Pitt, Morrice, et al., 2006). Fig. 3 provides a pictorial summary of key overlaps between H2O2 and oxidized lipid signaling. The overlap occurs in signaling pathways involving covalent modifications, not in those where oxidized lipids interact noncovalently with receptors, as the ligand structures are completely different. It is likely that additional synergy occurs between the different types of redox signaling; for example, 4-HNE strongly induced intracellular hydrogen peroxide production, and this could contribute to the activation of the JNK MAP kinase pathway (Uchida et al., 1999), while similar interplay has been reported in tumor cell responses (Bauer & Zarkovic, 2015). The field of biological effects of lipid oxidation and lipoxidation is currently much in the spotlight, as demonstrated by recent special issues on this topic. Free Radical Biology and Medicine had a special issue on “4-Hydroxynonenal and related lipid peroxidation products” edited by Poli and Zarkovic in 2017, and the second editor was responsible for Antioxidants and Second Messengers of Free Radicals in the journal in Antioxidants in 2018. Pérez-Sala and Domingues have edited a special issue on “Lipoxidation targets: From basic mechanisms to pathophysiology” in Redox Biology, while Redox Lipidomics and Adductomics - Advanced Analytical Strategies to Study Oxidized Lipids and Lipid-Protein Adducts will be published in Free Radical Biology and Medicine in 2019.

Abbreviations 4-HDDE 4-hydroxy-2E,6Z-dodecadienal 4-HNE 4-hydroxy-2E-nonenal 15d-PGJ2 15-deoxy-Δ-12,14-prostaglandin J2 cyPG cyclopentenone prostaglandin DAMP damage-associated molecular pattern eoxPL enzymatically formed oxidized phospholipids HOOA-PC 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero-3phosphocholine KOdiAPC 1-palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3phosphocholine) LPS lipopolysaccharide (endotoxin) LXR Liver X receptor MDA malondialdehyde oxPAPA oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphate oxPAPC oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine

­References

oxPAPG oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3phosphoglycerol oxPAPS oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphoserine oxPDHPC oxidized 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3phosphocholine oxPL oxidized phospholipid oxPLPC oxidized 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine PAF platelet-activating factor PAMP pathogen-associated molecular pattern PAzPC 1-palmitoyl-2-azealoyl-sn-glycero-3-phosphocholine PECPC 1-palmitoyl-2-(5,6-epoxyisoprostane A2)-sn-glycero-3phosphocholine PEIPC 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3phosphocholine PGA2 prostaglandin A2 PGPC 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine PKA/PKC protein kinase A or C POVPC 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine PPAR peroxisome proliferator-activated receptors PTP protein tyrosine phosphatase TLRs toll-like receptors

­Acknowledgments The author has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement number 675132 www.masstrplan.org.

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