Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewSpecialized pro-resolving lipid mediators in the inflammatory response: An update
Research Highlights
►The resolution of inflammation is actively regulated by specialized pro-resolving mediators (SPM). ►SPM are lipid mediators derived from arachidonic acid and omega-3 poly-unsaturated fatty acids. ►SPM are formed enzymatically during resolution of inflammation. ►SPM include lipoxins, resolvins, protectins, and maresins.
Section snippets
The inflammatory response
The inflammatory response is a local reaction of the vasculature towards a disturbance of tissue homeostasis incurred by damage to tissue structure and infection [1], [2], [3]. Changes in local blood vessel perfusion and permeability permit the directional extravasation of circulating leukocytes that achieve tissue disinfection, and of a range of plasma proteins which play distinct roles in regulating the inflammatory process. Structural alterations of tissue structure that activate the
The “front and back” of acute inflammation
Conserved physiological mechanisms limit the extent and duration of the inflammatory response [4], [24], [25]. These mechanisms can counter-regulate the extent of inflammation (or anti-inflammation), and/or promote the active termination or resolution of inflammation [4], [24]. The former encompasses those mechanisms activated to reduce the rate of granulocyte recruitment to the inflammatory focus and limit their state of activation. The latter comprises the active removal of the granulocytic
Lipoxins and aspirin
Lipoxin A4 (LXA4; (5S,6R,15S-trihydroxy-eicosa-7E,9E,11Z,13E-tetraenoic acid) is a central anti-inflammatory lipid mediator autacoid which plays an important function in determining the extent of granulocyte (neutrophil and eosinophil) accumulation and activation during inflammation. The formation of LXA4 is achieved by transcellular biosynthesis via two sequential oxygenation reactions of arachidonic acid (AA; Fig. 2) catalyzed by lipoxygenases present in interacting cell types, with one of
Specialized pro-resolving lipid mediators (SPM) derived from omega-3 poly-unsaturated fatty acids
A number of enzymatically oxygenated lipid mediators derived from ω-3 poly-unsaturated fatty acids (PUFA), such as EPA and DHA, were recently identified to function as specialized pro-resolution mediators (SPM) that “turn off” the inflammatory response in an active fashion [30]. These mediators, named resolvins, protectins, and maresins, constitute novel families of autacoids with potent anti-inflammatory, tissue-protective, and resolution-stimulating functions. It is important to note that
E-series resolvins: resolvin E1 and resolvin E2
Specific bioactivity was uncovered in the resolving exudates that stopped PMN migration and was 100 times as potent as aspirin in vivo [86]. The active molecule was coined resolvin E1 based on its in vivo production in resolving murine exudates, potent stereoselective actions (demonstrated in vitro and in vivo) and its precursor substrate EPA. Hence, it was important to consider the biosynthetic routes involved in the production of this and related molecules in human cell types. After
D-series resolvins
Given the ability of acetylated COX-2 to accept both AA and EPA as substrates for a single oxygenation reaction to form epimeric fatty acid hydroperoxides, DHA was subsequently tested and recognized as a substrate for acetylated COX-2 as well [92]. In this case oxygen is incorporated at carbon 17, forming a 17R-hydroperoxy group-containing DHA-derived intermediate that when reduced was shown to be 17R-hydroxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid (17R-HpDHA) (Fig. 4). The introduction of
Protectins and maresins
Although transcellular biosynthesis is recognized to be an important requirement for the formation of specific anti-inflammatory and pro-resolution lipid mediators, such as SPM, recent evidence is provided that a single cell type can also form oxygenated lipid mediators with potent counter-regulatory actions. The first pathway involves a 15-lipoxygenase-type I catalyzed formation of the same 17S-hydroperoxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid product required for D-series resolvin
Docosapentaenoic acid-derived resolvin-like products
Another ω-3 double-bond-containing PUFA, ω-3 docosapentaenoic acid (DPA; 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid) has recently been found to be an efficient substrate for oxygenation by 5-, 12-, and 15-lipoxygenases. A number of mono- and dihydroxy fatty acids derived from DPA were identified [129], [130]. Some of these hydroxy products display structural properties akin to pro-resolving protectin D1/NPD1 derived from DHA.
Also the ω-6 double-bond isomer docosapentaenoic acid (ω-6 DPA; 4Z,7Z,10Z
Gauging resolution: quantitative indices
Employing a widely used murine model of self-resolving acute inflammation activated by intraperitoneal administration of zymosan A, we earlier provided a definition of the inflammatory response in a set of quantifiable indices which can be relatively easily measured experimentally (Fig. 1) [89]. A close inspection of these indices for inflammation and resolution indicated that locally administered ATLa2, a stable 15-epi-LXA4 analog, potently reduced inflammation, indicating a significant
Specific molecular events during resolution of the inflammatory response
Recent studies indicate that distinct molecular processes are activated during the resolution phase of inflammation [89]. In addition to the cellular events which characterize resolution, such as leukocyte apoptosis, efferocytosis and egress, a parallel proteomic and mediator lipidomic study of the murine peritonitis model has indicated that distinct molecular events are also activated just prior to and during the resolution interval [89], [90], which can be summarized as follows: i) lipid
Substrate availability: mobilization for resolving exudates
The rapid changes in local blood vessel perfusion and permeability which occur during the early phase of the inflammatory response not only permit directional extravasation of circulating leukocytes and plasma proteins, but also may play an important role in the provision of substrate for SPM biosynthesis. In zymosan-stimulated peritonitis exudate levels of free unacylated ω-3 PUFA AA, EPA, and DHA increase rapidly, reaching maximal levels around 2–4 h (Fig. 1) [89]. Systemically administered
Concluding remarks and further directions
The formation of endogenous autacoids derived from ω-3 PUFA may explain in part the well-known, essential roles of the ω-3 PUFA in human health and disease. More importantly the contribution of novel SPM to the benefits derived from dietary ω-3 FA are beginning to be appreciated with the identification of resolvins as potent autacoids that regulate the resolution phase of the acute inflammatory response [148]. The resolution phase of inflammation has its own regulation involving specific
Conflict of interest statement
The author C.N.S. is an inventor on patents assigned to Brigham and Women's Hospital and Partners HealthCare on the composition of matter, uses, and clinical development of anti-inflammatory and pro-resolving agents. These are licensed for clinical development. C.N.S. retains founder stock in Resolvyx Pharmaceuticals.
Acknowledgements
Work reviewed here in the C.N.S. laboratory was sponsored in part by the National Institutes of Health USA grant nos. GM38765, DE 019938 and DK07448. G. Bannenberg was supported by a Postdoctoral Fellowship from the Arthritis Foundation, and is a Ramón y Cajal fellow at the Centro Nacional de Biotecnología/CSIC, Madrid, Spain. We thank Mary Small for excellent assistance in the preparation of this manuscript and our collaborators and colleagues for their efforts in the original reports reviewed
References (148)
- et al.
Sensing the microenvironment of the central nervous system: immune cells in the central nervous system and their pharmacological manipulation
Curr. Opin. Pharmacol.
(2008) - et al.
The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans
Cell
(2010) - et al.
Nonresolving inflammation
Cell
(2010) - et al.
Leukotriene E4: perspective on the forgotten mediator
J. Allergy Clin. Immunol.
(2009) - et al.
Changes in the levels of prostaglandins and thromboxane and their roles in the accumulation of exudate in rat carrageenin-induced pleurisy—a profile analysis using gas chromatography–mass spectrometry
Prostaglandins
(1982) Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution
Prostaglandins Leukot. Essent. Fatty Acids
(2005)- et al.
Resolution of inflammation
Int. J. Immunopharmacol.
(2000) - et al.
Omega-3 fatty acids as cancer chemopreventive agents
Pharmacol. Ther.
(1999) - et al.
A new deficiency disease produced by the rigid exclusion of fat from the diet
J. Biol. Chem.
(1929) Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale
Biochimie
(2009)
Biomarkers of DHA status
Prostaglandins Leukot. Essent. Fatty Acids
Sperm fatty acid composition in subfertile men
Prostaglandins Leukot. Essent. Fatty Acids
Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection
Prostaglandins Leukot. Essent. Fatty Acids
Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid
J. Lipid Res.
The “pro-apoptotic genies” get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexes
Chem. Biol. Interact.
Resolution of airway disease: removal of inflammatory cells through apoptosis, egression or both?
Trends Pharmacol. Sci.
Inflammatory macrophages, and not only neutrophils, die by apoptosis during acute peritonitis
Immunobiology
Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX
Prostaglandins Leukot. Essent. Fatty Acids
Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin
J. Biol. Chem.
Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart
Prostaglandins Other Lipid Mediat.
Selectivity of recombinant human leukotriene D4, leukotriene B4, and lipoxin A4 receptors with aspirin-triggered 15-epi-LXA4 and regulation of vascular and inflammatory responses
Am. J. Pathol.
Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor
J. Biol. Chem.
Peroxidative oxidation of leuco-dichlorofluorescein by prostaglandin H synthase in prostaglandin biosynthesis from polyunsaturated fatty acids
Biochim. Biophys. Acta
Fish oil feeding lowers thromboxane- and prostacyclin production by rat platelets and aorta and does not result in the formation of prostaglandin I3
Prostaglandins
Biosynthesis and biological activity of leukotriene B5
Prostaglandins
Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets
Blood
Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions
J. Biol. Chem.
Pathologic Basis of Disease
From inflammation to sickness: historical perspective
Arch. Immunol. Ther. Exp. (Warsz)
Resolution of inflammation: the beginning programs the end
Nat. Immunol.
Lipid autacoids in inflammation and injury responses: a matter of privilege
Mol. Interv.
Origin and physiological roles of inflammation
Nature
Lectures on Comparative Pathology of Inflammation
Regulation of adaptive immunity by the innate immune system
Science
Shedding light on vascular permeability during peritonitis: role of mast cell histamine versus macrophage cysteinyl leukotrienes
Inflamm. Res.
Phagocytosis of senescent neutrophils by human monocyte-derived macrophages and rabbit inflammatory macrophages
J. Exp. Med.
Wound healing: an overview of acute, fibrotic and delayed healing
Front. Biosci.
The transition from acute to chronic inflammation
Br. J. Dermatol.
Resolution of inflammation: state of the art, definitions and terms
FASEB J.
The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules
Nat. Immunol.
Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis
Thorax
Arachidonic acid metabolism: role in inflammation
Z. Rheumatol.
Dual action of prostaglandin E2 in allergic inflammation
Adv. Prostaglandin Thromboxane Leukot. Res.
Prostaglandin E2, prostaglandin I2 and the vascular changes of inflammation
Br. J. Pharmacol.
Resolution of acute inflammation and the role of apoptosis in the tissue fate of granulocytes
Clin. Sci. (Lond)
Neuroimmune regulation in immunocompetence, acute illness, and healing
Ann. NY Acad. Sci.
Neuroendocrine regulation of autoimmune/inflammatory disease
J. Endocrinol.
Physiology and immunology of the cholinergic antiinflammatory pathway
J. Clin. Invest.
Resolution phases of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways
Annu. Rev. Immunol.
Cited by (379)
The ELOVL6 homolog in Penaeus vannamei plays a dual role in fatty acid metabolism and immune response
2023, Molecular ImmunologyEffect of specialized pro-resolving lipid mediators in the regulation of vascular tone and inflammation in human saphenous vein
2023, Prostaglandins and Other Lipid MediatorsMicronized Acellular Matrix Biomaterial Leverages Eosinophils for Postinfarct Cardiac Repair
2023, JACC: Basic to Translational Science