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Eicosanoid storm in infection and inflammation

A Corrigendum to this article was published on 16 October 2015

This article has been updated

Key Points

  • Infection and injury cause controlled immune and inflammatory responses involving complex molecular signalling networks that lead to the production of bioactive lipid mediators.

  • Eicosanoids are bioactive lipid mediators derived from oxygenated polyunsaturated fatty acids.

  • Similar to cytokine signalling and inflammasome formation, eicosanoid signalling has been viewed primarily as a pro-inflammatory component of innate immunity.

  • Recent advances in lipidomics technologies have helped to elucidate unique eicosanoids and related docosanoids with anti-inflammatory and pro-resolution functions that are a key component of the inflammatory response.

  • Receptor activation initiated by Toll-like receptors (TLRs), purinergic receptors and other signalling pathways induced by infectious agents generates both pro-inflammatory and anti-inflammatory metabolites resulting in an eicosanoid storm.

  • Lipidomics has advanced our overall understanding of the inflammatory response and its therapeutic implications, and has suggested new pharmacological approaches.

Abstract

Controlled immune responses to infection and injury involve complex molecular signalling networks with coordinated and often opposing actions. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids constitute a major bioactive lipid network that is among the most complex and challenging pathways to map in a physiological context. Eicosanoid signalling, similar to cytokine signalling and inflammasome formation, has primarily been viewed as a pro-inflammatory component of the innate immune response; however, recent advances in lipidomics have helped to elucidate unique eicosanoids and related docosanoids with anti-inflammatory and pro-resolution functions. This has advanced our overall understanding of the inflammatory response and its therapeutic implications. The induction of a pro-inflammatory and anti-inflammatory eicosanoid storm through the activation of inflammatory receptors by infectious agents is reviewed here.

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Figure 1: Eicosanoid biosynthesis and receptor signalling.
Figure 2: Enzyme functional coupling, transcellular biosynthesis and eicosanoid class switching.
Figure 3: Inflammasome formation and caspase activation parallel lipoxin formation for a complete inflammatory response.
Figure 4: Therapeutics targeting eicosanoid pathways.

Change history

  • 16 October 2015

    In the version of this article that was originally published, the LIPID MAPS 'Glue' grant number included in the Acknowledgements was incorrect. The correct grant number is U54 GM069338. The authors apologize for this error, which has now been corrected online.

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Acknowledgements

E.A.D. thanks the US National Institutes of Health (NIH) for National Institute of General Medical Sciences (NIGMS) grants RO1 GM20501-39 and the LIPID MAPS “Glue” grant U54 GM069338 for support of research and scholarly activity and T32 GM007752 for support of graduate training for P.C.N..

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Supplementary information

Supplementary information S1 (figure)

Enzymes in the cyclooxygenase pathway generate prostaglandins, thromboxanes, and lipoxins from arachidonic acid. (PDF 174 kb)

Supplementary information S2 (figure)

Enzymes in the lipoxygenase pathway generate leukotrienes, HETEs, and hepoxilins from arachidonic acid. (PDF 182 kb)

Supplementary information S3 (figure)

Enzymes in the cytochrome P450 epoxyhydrolase pathway generate epoxides and dihydroxy polyunsaturated fatty acids (PUFAs) from arachidonic acid. (PDF 142 kb)

Glossary

Eicosanoids

Bioactive oxygenated polyunsaturated fatty acids containing 20 carbons.

Non-steroidal anti-inflammatory drugs

(NSAIDs). Drugs, such as aspirin and naproxen, that are used to ablate the inflammatory response. They work by inhibiting cyclooxygenase 1 (COX1) and COX2, thereby blocking the biosynthesis of prostaglandins including thromboxane.

Docosanoids

Bioactive oxygenated polyunsaturated fatty acids containing 22 carbons.

Inflammasome

A molecular complex of several proteins that, upon assembly, cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18, thereby producing the active forms of these pro-inflammatory cytokines.

Toll-like receptor

(TLR). A pattern recognition receptor that recognizes conserved molecules from pathogens, such as lipopolysaccharide, and initiates innate immune responses.

Peroxisome proliferator-activated receptor-α

(PPARα). Member of a family of nuclear receptors that participate in the regulation of cellular metabolism and differentiation. PPARs have anti-inflammatory properties as they regulate the availability of limited cofactors or block promoters of pro-inflammatory genes.

Specialized pro-resolving mediators

(SPMs). Eicosanoids and docosanoids that promote efferocytosis and also inhibit neutrophil diapedesis and pro-inflammatory cytokine expression. SPMs include lipoxins, resolvins, protectins, maresins and the newly discovered maresin conjugates in tissue regeneration (MCTR) sulfido-conjugate series.

Caecal ligation and puncture

An experimental model of peritonitis in rodents in which the caecum is ligated and then punctured, thereby forming a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Myeloperoxidase

(MPO). An enzyme that is most highly expressed by neutrophils, where it is stored in azurophilic granules. MPO produces hypochlorous acid from hydrogen peroxide and chloride ions during the respiratory burst in neutrophils.

Purinergic receptors

A family of plasma membrane-bound molecules that are involved in several known cellular functions, such as vascular reactivity, apoptosis and cytokine secretion.

Resolvins

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

Metabolons

In the context of this Review refers to complexes of multiple enzymes (bound or in close proximity) that coordinately synthesize eicosanoids and docosanoids, which is often dependent on receptor activation and cell–cell transfer of intermediates.

Fluxomics

The study of the flux or the change in the concentration of products and/or metabolites in a biosynthetic pathway in a cell as a function of time.

Lipoxins

A class of eicosanoids, comprising LXA4 and LXB4, that are produced by lipoxygenase-mediated metabolism of arachidonic acid. They are trihydroxytetraene-containing structures with potent biological activities in the resolution of inflammation.

Eicosanoid class switching

A process by which pro-inflammatory eicosanoid synthesis changes to anti-inflammatory or pro-resolution eicosanoid and docosanoid synthesis.

Efferocytosis

The phagocytic clearance of apoptotic cells (from the Latin word effero, meaning to take to the grave or bury) before they undergo secondary necrosis. The process usually triggers an anti-inflammatory response.

Necrotic cell death

A form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves the loss of cell integrity and release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Depending on the context, the self-antigens that are released by necrosis could become immunogenic.

Lyme disease

A disease caused by the bacterium Borrelia burgdorferi or other Borrelia spp. that are transmitted to humans via the bites of infected black-legged ticks. Symptoms can include skin rash, fever, fatigue, headache, muscle pain, stiff neck, and swelling of the knee and other large joints. Most cases can be successfully treated with antibiotics.

UPLC/MS–MS technology

Ultra-high performance liquid chromatography (UPLC) combined with tandem mass spectrometry (MS–MS) for chemical separation and quantitative analysis.

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Dennis, E., Norris, P. Eicosanoid storm in infection and inflammation. Nat Rev Immunol 15, 511–523 (2015). https://doi.org/10.1038/nri3859

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