TY - JOUR
AU - Arita, Makoto
AB - Abstract Acute inflammation is an indispensable host response to foreign challenges or tissue injury. In healthy conditions, inflammatory processes are self-limiting and self-resolving, suggesting the existence of endogenous mechanisms for the control of inflammation and resolution. A comprehensive understanding of the cellular and molecular events of a well-orchestrated inflammatory response is required, and recent studies have uncovered the roles of endogenous lipid mediators derived from polyunsaturated fatty acids (i.e. lipoxins, resolvins, protectins) in controlling the resolution of inflammation. This review presents recent advances in understanding the formation and action of these mediators, especially focusing on the LC-MS/MS-based lipidomics approach and the emerging roles of eosinophils and eosinophil-derived lipid mediators in controlling acute inflammation and resolution. eosinophil, lipid mediator, metabolomics, n-3 PUFA, resolution of inflammation Acute inflammation is an indispensable host response to insult or tissue injury. However, in many human diseases, uncontrolled inflammation is suspected as a key component of pathogenesis (1). Excessive or inappropriate inflammatory responses can cause local tissue damage and remodelling which contribute to a range of chronic diseases. In healthy individuals, acute inflammation is self-limiting and has an active termination program (2). Therefore, the identification of such endogenous anti-inflammatory and/or pro-resolution mechanisms is of wide interest. Polyunsaturated fatty acids (PUFAs) exhibit a range of biological effects, many of which are mediated through the formation and actions of lipid mediators such as prostaglandins (PGs), leukotrienes (LTs), lipoxins (LXs), resolvins (Rvs) and protectins (3). The lipid mediators are potent endogenous regulators of inflammation and related diseases. To better understand the molecular and cellular mechanisms underlying the coordinated processes of inflammation and resolution, it is important to know when and where lipid mediators are formed in the inflammatory sites and which ones are formed. To this end, we developed an LC-ESI-MS/MS-based lipidomics system geared to the comprehensive analyses of lipid mediators with simultaneous and quantitative measurements. Using this system, we revealed a coordinated class switching of PUFA-derived mediators in the course of acute inflammation, and a novel role of eosinophils and eosinophil-derived lipid mediators in the resolution of acute peritonitis. PUFA-Derived Lipid Mediators: Formation and Action PUFA-derived lipid mediators are formed by enzymatic oxidation through the action of cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 monooxygenases (CYP). Arachidonic acid (AA, 20:4 n-6) is a common precursor of many eicosanoids, which are bioactive lipid mediators that control inflammatory responses. When cells are stimulated, AA is released from membrane phospholipids by phospholipase A2 (PLA2), which hydrolyzes the acyl ester bond. This is the first step in the AA cascade, and is the overall rate-determining step in the generation of eicosanoids. Mammals have three types of PLA2, which are classified as secretory, cytoplasmic and calcium-independent PLA2s (sPLA2s, cPLA2s, iPLA2s), respectively (4, 5). The different types of PLA2 are regulated differently and are expressed in different tissues. Unesterified intracellular AA is immediately metabolized by either COX, LOX or CYP. The COX pathway leads to the formation of PGs and thromboxanes (TXs), the LOX pathway leads to LTs, LXs and hydroxyeicosatetraenoic acids (HETE), and the CYP pathway leads to HETEs and epoxyeicosatrienoic acids (EET) (Fig. 1). As a class, these molecules act as autacoids that are rapidly synthesized in response to specific stimuli, act quickly at the immediate locality, and remain active for only a short time before degradation. Fig. 1 View largeDownload slide Eicosanoid production from AA. PLA2 cleaves the ester bond of phospholipids to release AA. Free AA is used as a substrate for the LOX, COX and CYP pathways. The COX pathway produces PGs and TX. The LOX pathway produces LTs, LXs and HETEs. The CYP pathway produces EETs and HETEs. Fig. 1 View largeDownload slide Eicosanoid production from AA. PLA2 cleaves the ester bond of phospholipids to release AA. Free AA is used as a substrate for the LOX, COX and CYP pathways. The COX pathway produces PGs and TX. The LOX pathway produces LTs, LXs and HETEs. The CYP pathway produces EETs and HETEs. AA-derived eicosanoids are important in many physiological processes. Under non-disease conditions, PGs contribute to the maintenance of homeostasis, e.g. they have cytoprotective roles in the gastric mucosa, respiratory tract and renal parenchyma. PGs are also involved in pro-inflammatory processes, and are responsible for many of the hallmark signs of inflammation such as heat, redness, swelling and pain (6). COX occurs in two isoforms, called the constitutive isoform (COX-1) and the inducible isoform (COX-2) (7). These enzymes may contribute to the production of different sets of eicosanoids at different locations at different times. The LOX pathway represents another major pathway to produce LTs and LXs. Mammals have at least three LOXs, 5 -, 12 - and 15-LOX present in mammalian systems (8, 9). 5-LOX-derived LTs (LTB4, cysteinyl LTs) are involved in pro-inflammatory processes such as neutrophil infiltration, increased vascular permeability and smooth muscle contraction (10). In contrast, 5 - and 15-LOX-derived LXA4 counter-regulates the pro-inflammatory processes and may be important in the resolution of inflammation (11). An imbalance in lipoxin-leukotriene homeostasis may be a key factor in the pathogenesis of inflammatory diseases. The epoxygenation of AA by CYP generates EETs, which may have roles in regulation of smooth muscle cells and vascular tone (12). Many of the eicosanoids signal via seven-transmembrane G protein-coupled receptors (GPCRs) (6, 13). Eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) are n-3 PUFAs that are abundant in fish oils. EPA-derived mediators include 3-series PGs, 5-series LTs and LXs, hydroxyeicosapentaenoic acids (HEPE), and epoxy-eicosatetraenoic acids (EpETE) (Fig. 2). DHA is also converted to hydroxydocosahexaenoic acids (HDoHE) and epoxy-fatty acids by enzymatic oxidation. Dietary supplementation of n-3 PUFA has beneficial effects in many inflammatory disorders, including cardiovascular disease, arthritis, colitis and metabolic syndrome (14). Also, elevation in n-3 PUFA levels in n-3 desaturase (fat-1) transgenic mice protected against inflammatory disease models (15). N-3 PUFAs are thought to act via several mechanisms. One role is to serve as an alternative substrate for COX or LOX, resulting in the production of less potent products (16). Another role is to be converted to potent anti-inflammatory and protective mediators. For example, E-series Rvs are produced from EPA, and D-series Rvs, protectin and maresin are produced from DHA [reviewed in (17)] (Fig. 2). Rvs, protectin and maresin are distinct families of local mediators identified in the resolving exudates of acute inflammation. They were initially identified using a systems approach with LC-MS/MS-based lipidomics and then complete structural elucidation of the bioactive mediators was achieved. RvE1 (5 S,12 R,18 R-trihydroxy-6 Z,8 E,10 E,14 Z,16 E-EPE) and RvE2 (5 S,18 R-dihydroxy-6 E,8 Z,11 Z,14 Z,16 E-EPE) are biosynthesized via the 5-LOX pathway from a precursor, 18-hydroxyeicosapentaenoic acid (18-HEPE) (18–21). From DHA, Protectin D1 (10 R,17 S-dihydroxy-docosa-4 zZ,7 Z,11 E,13 E,15 Z,19 Z-hexaenoic acid; PD1) is formed via the 15-LOX pathway (22), and maresin 1 (7 S,14 S-hydroxy-docosa-4 Z,8 E,10 E,12 Z,16 Z,19 Z-hexaenoic acid; MaR1) is formed via the 12-LOX pathway (23). D-series Rvs such as RvD1 (7 S, 8 R, 17 S-trihydroxy-docosa-4 Z,9 E,11 E,13 Z,15 E,19 Z-hexaenoic acid) and RvD2 (7 S,16 R,17 S-trihydroxy-docosa-4 Z,8 E,10 Z,12 E,14 E,19 Z-hexaenoic acid) are formed via combination of 5 - and 15-LOX pathways from DHA (24, 25). These mediators, not only act as potent anti-inflammatory lipid mediators limiting neutrophil influx, but also promote resolution of inflammation by stimulating the clearance of apoptotic cells and inflammatory debris by macrophages (25–27). These mediators possess stereoselective properties and display potencies in the low nanomolar range in many mammalian systems. As part of their molecular mechanism, these mediators exert their potent actions via cell-surface receptors such as GPCRs and transient receptor potential (TRP) ion channels (21–23). For example, Rvs differentially interact with distinct GPCRs (e.g. GPR32, ALX/FPRL1, ChemR23, BLT1, etc.) to prevent excessive inflammation and elicit pro-resolving signals by promoting macrophage phagocytic activity and clearance of apoptotic cells and inflammatory debris (28, 29). Also specific Rvs inhibit inflammatory and neuropathic pain in mice and suppress distinct TRP channels (e.g. TRPA1, V1, V3, V4) to control selective pain modalities (30, 31). To date, receptor candidates for PD1 or MaR1 have not been reported. Neither RvE1 nor RvD1 directly activated nuclear receptors such as peroxisome proliferator-activated receptor (PPAR)-α, γ and δ, or retinoid X receptor α (RXR) compared to known nuclear receptor agonists (29). Fig. 2 View largeDownload slide Eicosanoid, docosanoid and hydroxy-fatty acid production from AA, EPA and DHA. Fig. 2 View largeDownload slide Eicosanoid, docosanoid and hydroxy-fatty acid production from AA, EPA and DHA. LC-ESI-MS/MS-Based Lipidomics A powerful method for the analysis of mono- and polyhydroxylated fatty acids is liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). Electrospray ionization (ESI) is a soft ionization technology used to form either positive or negative ions without derivatization and decomposition. In the case of fatty acid-derived mediators, ESI results in the removal of a proton to form [M-H]− carboxylate ions. A triple quadrupole mass spectrometer is capable of carrying out an MS/MS method called multiple reaction monitoring (MRM). A specified precursor ion is selected according to its mass-to-charge ratio (m/z) in the first quadrupole mass filter, and is fragmented into product ions in the second chamber by collision-induced dissociation (CID). Then the third quadrupole mass filter is locked on its specified product ion. We developed a comprehensive LC-ESI-MS/MS method that can simultaneously detect and quantify more than 250 PUFA metabolites including PGs, LTs, LXs, Rvs, protectins and other AA-, EPA-, DHA-derived products (36, 37). Representative MRM chromatograms are depicted in Fig. 3. The LC-MS/MS system using MRM mode provides structure-specific signal detection and further improves the quantification limits when combined with high-resolution LC separations. Fig. 3 View largeDownload slide Flow chart depicting the system of LC-ESI-MS/MS-based lipidomics. After solid phase extraction, samples are separated by HPLC, and fatty acid metabolites are detected and quantified by MRM using triple quadrupole MS/MS. Representative MRM chromatograms of fatty acid metabolites are depicted. Fig. 3 View largeDownload slide Flow chart depicting the system of LC-ESI-MS/MS-based lipidomics. After solid phase extraction, samples are separated by HPLC, and fatty acid metabolites are detected and quantified by MRM using triple quadrupole MS/MS. Representative MRM chromatograms of fatty acid metabolites are depicted. Mediator Lipidomics in Acute Inflammation and Resolution The local inflammatory response is characterized by a sequential release of mediators and the recruitment of different types of leukocytes (32). Acute inflammation is characterized by edema formation and the initial recruitment of neutrophils followed by the recruitment of monocytes that differentiate into macrophages. Lipid mediators such as PGs and LTs, and cytokines and chemokines coordinatedly regulate the initial events of acute inflammation. Also the resolution of acute inflammation is an active process that is controlled by endogenous pro-resolving mediators, thereby leading to the efficient clearance of inflammatory leukocytes and exudates, and restoration of the inflamed tissue to homeostasis (2). In contained inflammatory exudates, coordinated lipid mediator class switching occurs in the course of acute inflammation and resolution (33–35). To better understand the molecular and cellular mechanisms underlying the coordinated processes of inflammation and resolution, we applied LC-ESI-MS/MS-based mediator lipidomics to the self-resolving acute inflammation model, namely murine zymosan-induced peritonitis (36). Temporal and quantitative differences in the lipid mediator profiles were observed in the course of acute inflammation and resolution. The maximum levels of 5-LOX products such as LTB4 were observed in initiation phase, and subsequently subsided during the resolution. In contrast, the levels of 12/15-LOX products such as DHA-derived mediator PD1 were low at the initiation, then gradually increased during the resolution phase (Fig. 4A). PD1 not only acts as potent anti-inflammatory lipid mediators limiting neutrophil influx but also promotes the resolution of inflammation by stimulating macrophage ingestion of apoptotic cells and inflammatory debris, and by increasing the movement of phagocytes into draining lymph nodes (26). Thus, the endogenous cellular source of PD1 in the resolution phase was of interest. Recently, eosinophils were found to be the major source of PD1 biosynthesis in the early phase of resolution (36). The predominant population expressing 12/15-LOX in the early resolution phase was eosinophils, and isolated eosinophils produced a significant amount of PD1 when stimulated ex vivo. Also, in vivo depletion of eosinophils by anti-interleukin(IL)-5 antibody increased the number of neutrophils in inflammatory exudates, and reduced the number of phagocytes moving from the inflamed peritoneum to the draining lymph nodes, both of which showed a resolution deficit. LC-MS/MS-based lipidomics analysis revealed that the amounts of 12/15-LOX-derived mediators dramatically decreased in eosinophil-depleted mice, whereas the amounts of COX and 5-LOX-derived products did not differ between the two groups. Furthermore, the resolution deficit caused by eosinophil depletion was rescued by eosinophil restoration or local administration of PD1, and eosinophils deficient in 12/15-LOX were unable to rescue the resolution phenotype. Collectively, eosinophils are recruited to the inflamed loci in the early resolution phase, where they locally produce resolution mediators including PD1 via a 12/15-LOX-initiated biosynthetic route, and play roles in promoting resolution of acute inflammation (36) (Fig. 4B). Fig. 4 View largeDownload slide Emerging roles of eosinophils and eosinophil-derived lipid mediators in the resolution of acute inflammation. (A) Temporal and quantitative differences of lipid mediator profiles in the course of acute inflammation and resolution. 5-LOX products such as LTB4 are present in the initiation phase, and 12/15-LOX products such as PD1 are increased during the resolution phase. (B) Eosinophils are recruited in the early resolution phase, where they locally produce resolution mediators such as PD1 via a 12/15-LOX-initiated biosynthetic route, and play roles leading to the efficient clearance of inflammatory leukocytes and exudates (36). Fig. 4 View largeDownload slide Emerging roles of eosinophils and eosinophil-derived lipid mediators in the resolution of acute inflammation. (A) Temporal and quantitative differences of lipid mediator profiles in the course of acute inflammation and resolution. 5-LOX products such as LTB4 are present in the initiation phase, and 12/15-LOX products such as PD1 are increased during the resolution phase. (B) Eosinophils are recruited in the early resolution phase, where they locally produce resolution mediators such as PD1 via a 12/15-LOX-initiated biosynthetic route, and play roles leading to the efficient clearance of inflammatory leukocytes and exudates (36). Novel Bioactive Products Derived from Eosinophils Since eosinophils function to promote resolution by locally producing pro-resolving mediators such as PD1, we questioned whether other mediator(s) with potent anti-inflammatory properties could be formed by eosinophils. To this end, isolated leukocytes were incubated with fatty acid precursors and the lipids were analysed by LC-MS/MS. Several hydroxylated products were identified using MRM with established or predicted precursor-product ion pairs. RvE1 and RvE2 are biosynthesized by human polymorphonuclear leukocytes (PMNs) via the 5-LOX pathway from a common precursor 18-HEPE (18–21). 18-HEPE formation in vivo is related to dietary intake of EPA (19), and a recent study demonstrated two parallel stereospecific pathways, 18 R- and 18 S-, in the biosynthesis of E series Rvs both in human sera and murine exudates (21). Side-by-side MRM chromatograms of products from human PMN and eosinophil incubations with 18-HEPE demonstrated that human PMNs converted 18-HEPE into RvE1 and RvE2, and in comparison, eosinophils converted 18-HEPE into novel 8,18-dihydroxy-EPE (8,18-diHEPE), 11,18-diHEPE, 12,18-diHEPE and 17,18-diHEPE via the 12/15-LOX pathway (Fig. 5). Among them, two stereoisomers of 17,18-diHEPE, collectively termed resolvin E3 (RvE3), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in zymosan-induced peritonitis. The basic structures of these bioactive products were identified as 17,18 R/S-dihydroxy-5 Z,8 Z,11 Z,13 E,15 E-EPE, denoted 18 R-RvE3 and 18 S-RvE3, respectively. Both 18 R- and 18 S-RvE3 inhibited neutrophil chemotaxis in vitro at low nanomolar concentrations (37). Fig. 5 View largeDownload slide Biosynthesis of a novel eosinophil-derived mediator RvE3. EPA-derived 18-HEPE is converted via the sequential actions of LOX, which leads to formation of E series Rvs. 5-LOX expressed in PMNs converts 18-HEPE into RvE1 and RvE2 (19–21). 18-HEPE is also converted by eosinophils via the 12/15-LOX pathway into potent anti-inflammatory mediator RvE3 (17,18-diHEPE) together with other novel metabolites 8,18-diHEPE, 11,18-diHEPE and 12,18-diHEPE (37). Fig. 5 View largeDownload slide Biosynthesis of a novel eosinophil-derived mediator RvE3. EPA-derived 18-HEPE is converted via the sequential actions of LOX, which leads to formation of E series Rvs. 5-LOX expressed in PMNs converts 18-HEPE into RvE1 and RvE2 (19–21). 18-HEPE is also converted by eosinophils via the 12/15-LOX pathway into potent anti-inflammatory mediator RvE3 (17,18-diHEPE) together with other novel metabolites 8,18-diHEPE, 11,18-diHEPE and 12,18-diHEPE (37). Perspectives Determining the contributions of eosinophils to the biosynthesis of RvE3 and other 12/15-LOX-derived mediators such as PD1 is of interest because such mediators have roles in controlling acute inflammation and resolution. Eosinophils are thought to primarily assist in the host defense against parasitic infection through the release of cytotoxic products such as major basic protein and eosinophil-derived peroxidase (38). The release of these products also induces tissue damage and dysfunction, especially under allergic conditions. It is of interest whether eosinophils in the resolution phase represent a distinct subset. Besides eosinophils, 12/15-LOX is expressed in tissue-resident macrophages, dendritic cells, mast cells and airway epithelial cells (9). Also, the expression level of 12/15-LOX is upregulated in various cell types by Th2 cytokines including interleukin(IL)-4 and IL-13 (9). Cells expressing 12/15-LOX might be involved in regulating inflammatory responses by locally producing anti-inflammatory lipid mediators such as PD1 and RvE3. This is consistent with the finding of exacerbated inflammatory responses in 12/15-LOX-deficient mice in several disease models (39–42). Mediator lipidomics concerns the simultaneous and quantitative analysis of bioactive lipid mediators in biological systems. When combined with proteomic, transcriptomic and genomic profiles (multi-omics profiling), it can greatly assist in understanding the role of lipid mediators in certain biological and/or pathological conditions. This technology could potentially identify the metabolic fingerprint of a disease for clinical diagnosis and treatment. Moreover, the recently identified Rv and protectin families and the LX class of eicosanoids constitute a new group of endogenous mediators with potent anti-inflammatory and tissue-protective actions. They could lead to the development of resolution agonist-based therapeutics for many human diseases when sustained inflammation and impaired resolution are suspected as key components of pathogenesis. Funding This work was supported by Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology, and a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Conflict of interest None declared. Abbreviations Abbreviations COX, cyclooxygenase CYP cytochrome P450 monooxygenase DHA docosahexaenoic acid EPA eicosapentaenoic acid HEPE hydroxyeicosapentaenoic acid LOX lipoxygenase LT leukotriene LX lipoxin MRM multiple reaction monitoring PD1 protectin D1 PG prostaglandin PMN polymorphonuclear leukocytes PUFA polyunsaturated fatty acid Rv resolvin References 1 Nathan C,  Ding A.  Nonresolving inflammation,  Cell ,  2010, vol.  140 (pg.  871- 882) Google Scholar CrossRef Search ADS PubMed  2 Serhan CN,  Brain SD,  Buckley CD,  Gilroy DW,  Haslett C,  O'Neill LAJ,  Perretti M,  Rossi AG,  Wallace JL.  Resolution of inflammation: state of the art, definitions and terms,  FASEB J. ,  2007, vol.  21 (pg.  325- 332) Google Scholar CrossRef Search ADS PubMed  3 Stables MJ,  Gilroy DW.  Old and new generation of lipid mediators in acute inflammation and resolution,  Prog. 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TI - Mediator lipidomics in acute inflammation and resolution
JO - The Journal of Biochemistry
DO - 10.1093/jb/mvs092
DA - 2012-08-24
UR - https://www.deepdyve.com/lp/oxford-university-press/mediator-lipidomics-in-acute-inflammation-and-resolution-B40zCda81r
SP - 313
EP - 319
VL - 152
IS - 4
DP - DeepDyve
ER -