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  • Review Article
  • Published:

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

Key Points

  • Complete resolution of an acute inflammatory response and its return to homeostasis are essential for healthy tissues. Resolution of acute inflammation is an active process, not just passive termination of inflammation.

  • Novel families of lipid mediators are generated in inflammatory exudates during the resolution phase and they can promote and/or accelerate resolution. These mediators include the lipoxins, and the resolvins and (neuro)protectins, which are derived from the omega-3 essential fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

  • The pro-resolution lipid mediators are agonists of resolution, with multiple mechanisms of action at the tissue level: they 'stop' neutrophil and eosinophil infiltration; stimulate non-phlogistic recruitment of monocytes; enhance macrophage phagocytosis of apoptotic neutrophils; increase the exit of phagocytes from the inflammatory site to the lymphatics; and stimulate mucosal antimicrobial defence.

  • Pro-resolution and anti-inflammation are not equivalent; pro-resolution programmes stimulate and activate endogenous pathways to terminate inflammation.

  • Pro-resolution lipid mediators exert their protective activity at multiple levels in a range of cell types and in complex disease systems.

  • Pro-resolution lipid mediators promote resolution of inflammation in oral, lung, ocular, kidney, neural and gastrointestinal inflammatory diseases, as well as in ischaemia–reperfusion injury and angiogenesis.

Abstract

Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.

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Figure 1: Decision paths in acute inflammation: resolution or chronic inflammation and the roles of endogenous chemical mediators.
Figure 2: Dual anti-inflammatory and pro-resolution actions of specific lipoxins, resolvins and protectins.
Figure 3: Mechanisms of action of lipoxin A4 and resolvin E1: regulation at multiple levels via G-protein-coupled receptors (GPCRs).
Figure 4: Resolution indices pinpoint the mechanism of action of anti-inflammatory and pro-resolution lipid mediators in tissues.

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Acknowledgements

We thank M. H. Small for expert assistance in manuscript preparation. This study was supported in part by the National Institutes of Health, USA; GM38765 (C.N.S.), DK074448 (C.N.S.) and P50-DE016191 (C.N.S., T.E.V.D. and N.C.). We apologize to our colleagues if their original contributions are missed in the references owing to space limitations.

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Correspondence to Charles N. Serhan.

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C.N.S holds patents regarding resolvins, lipoxins and related compounds assigned to Brigham and Women's hospital that are licensed for clinical development. T.E.V.D. co-holds patents for clinical uses assigned to Boston University. Both portfolios are subjects of consulting agreements for C.N.S and T.E.V.D.

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An intracellular vesicle that results from the fusion of phagosomes, which enclose extracellular material that has been ingested, and lysosomes, which contain lytic enzymes.

Eicosanoids

A family of bioactive products that contain 20 (eicos in Greek) carbons. They are biosynthesized from arachidonic acid by the initial activities of either cyclooxygenases (isoforms COX1 or COX2) or lipoxygenases and downstream enzymatic reactions. There are several main classes of eicosanoids: prostaglandins, prostacyclins, thromboxanes, leukotrienes and lipoxins.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

Diapedesis

The migration of leukocytes across the endothelium, which occurs by squeezing through the junctions between adjacent endothelial cells. This is the last step in the leukocyte–endothelial-cell adhesion cascade that includes tethering, triggering, tight adhesion and transmigration.

Leukotrienes

A class of eicosanoids derived from the metabolism of arachidonic acid by the action of leukocyte 5-lipoxygenase and other enzymes. They have a conjugated triene double-bond structure and various pro-inflammatory activities, including leukocyte activation (by leukotriene B4) and bronchoconstriction (by leukotriene C4 and leukotriene D4).

Lipoxins

A class of eicosanoids that are produced by lipoxygenase-mediated metabolism of arachidonic acid. They are trihydroxytetraene-containing structures with potent biological activities in the resolution of inflammation.

Resolvins

Lipid mediators that are induced in the resolution phase following acute inflammation. They are synthesized from the essential omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Protectins

A family of docosahexaenoic acid (DHA)-derived mediators characterized by the presence of a conjugated triene double-bond structure and 22 carbons with 6 double bonds.

Exudate

Biological fluid that filters from the circulatory system into lesions or areas of inflammation. Exudate is characterized by a high content of plasma proteins, cells and cellular debris. Pus is an example of an exudate found in infected wounds and it contains bacteria and high concentrations of white blood cells.

Prostaglandins

Cyclopentane-ring-containing lipids derived from the metabolism of arachidonic acid by the action of cyclooxygenases and downstream synthase enzymes. They have a diverse range of biological activities and a well-recognized role in inflammation and pain.

Transcellular biosynthesis

The biosynthesis of biologically active mediators that involves two or more cell types, for example, when the necessary enzymes are differentially expressed by two or more cell types. For example, a donor cell converts a precursor compound (such as arachidonic acid, EPA and DHA) into an intermediate product. The acceptor cell then converts the intermediate product into the final active product. Transcellular biosynthesis therefore provides a means to produce mediators that neither cell type can generate alone.

G-protein-coupled receptors

(GPCRs). A large group of receptors that bind a diverse set of molecules, including chemokines, complement components, biologically active amines and neurotransmitters. GPCRs are seven-transmembrane-spanning receptors and are coupled to heterotrimeric, GTP-regulated signalling proteins composed of β and βγ subunits.

Statins

A class of drugs that inhibit the rate-limiting enzyme (3-hydroxy-3-methylglutaryl coenzyme A reductase) in the pathway of cholesterol biosynthesis. These molecules are mainly used as cholesterol-lowering drugs, but they also have immunoregulatory and anti-inflammatory properties.

Murine dorsal air pouch model

A well-characterized model for studying inflammatory responses. Air pouches are formed by subcutaneous injection of air into the back of a mouse, into which potential inflammatory stimuli, such as tumour-necrosis factor, can be added. Importantly, when the stimulus is titrated, inflammatory reactions undergo spontaneous resolution. These structurally contained compartments have been likened to the inflamed synovium.

Cytochrome P450 enzymes

A large and diverse superfamily of haemoproteins. Cytochrome P450 enzymes use a plethora of both exogenous and endogenous compounds as substrates. The most common reaction catalysed by cytochrome P450 is a monooxygenase reaction, that is, insertion of one atom of oxygen into an organic substrate while the other oxygen atom is reduced to water.

Alzheimer's disease

A degenerative neurological disease that is characterized by progressive deterioration of the brain, dementia, and the presence of senile plaques, neurofibrillary tangles and neuropil threads. Disease onset can occur at any age, and women seem to be affected more frequently than men.

Rabbit model of periodontitis

A model of periodontitis in rabbits induced by application of Porphyromonas gingivalis to ligatures tied to second premolars.

Alveolar bone

The thickened ridge of bone that forms the tooth socket surrounding the roots of teeth.

Ulcerative colitis

An inflammatory bowel disease characterized by chronic inflammation of the colon.

Age-related macular degeneration

A condition predominantly found in elderly adults in which the centre of the inner lining of the eye, known as the macula area of the retina, suffers thinning, atrophy and in some cases bleeding, and can result in loss of central vision.

Creatinine

A component of urine and the final product in the metabolism of creatine. An increase of creatinine in serum concentration is used as a marker of kidney dysfunction.

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Serhan, C., Chiang, N. & Van Dyke, T. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8, 349–361 (2008). https://doi.org/10.1038/nri2294

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