Controlled immune responses to infection and injury involve complex molecular signaling networks with coordinated and often opposing actions. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids constitute a major bioactive lipid network, which is among the most complex and challenging pathways to map in a physiological context. Eicosanoid signaling, similar to cytokine signaling and inflammasome formation, has been viewed as primarily 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- and anti-inflammatory eicosanoid storm through the activation of inflammatory receptors by infectious agents is reviewed.

Proinflammatory eicosanoids (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPM) are temporally regulated during infections. Here we show that human macrophage phenotypes biosynthesize unique lipid mediator signatures when exposed to pathogenic bacteria. E. coli and S. aureus each stimulate predominantly proinflammatory 5-lipoxygenase (LOX) and cyclooxygenase pathways (i.e., leukotriene B4 and prostaglandin E2) in M1 macrophages. These pathogens stimulate M2 macrophages to produce SPMs including resolvin D2 (RvD2), RvD5, and maresin-1. E. coli activates M2 macrophages to translocate 5-LOX and 15-LOX-1 to different subcellular locales in a Ca2+-dependent manner. Neither attenuated nor non-pathogenic E. coli mobilize Ca2+ or activate LOXs, rather these bacteria stimulate prostaglandin production. RvD5 is more potent than leukotriene B4 at enhancing macrophage phagocytosis. These results indicate that M1 and M2 macrophages respond to pathogenic bacteria differently, producing either leukotrienes or resolvins that further distinguish inflammatory or pro-resolving phenotypes.

Local mediators orchestrate the host response to both sterile and infectious challenge and resolution. Recent evidence demonstrates that maresin sulfido‐conjugates actively resolve acute inflammation and promote tissue regeneration. In this report, we investigated self‐limited infectious exudates for novel bioactive chemical signals in tissue regeneration and resolution. By use of spleens from Escherichia coli infected mice, self‐resolving infectious exudates, human spleens, and blood from patients with sepsis, we identified 2 new families of potent molecules. Characterization of their physical properties and isotope tracking demonstrated that the bioactive structures contained a docosahexaenoate backbone and sulfido‐conjugated triene or tetraene double‐bond systems. Activated human phagocytes converted 17‐hydro(peroxy)‐4Z,7Z,10Z,13Z,15E,19Z‐docosahexaenoic acid to these bioactive molecules. Regeneration of injured planaria was accelerated with nanomolar amounts of 16‐glutathionyl, 17‐hydroxy‐4Z,7Z,10,12,14,19Z‐docosahexaenoic acid and 16‐cysteinylglycinyl, 17‐hydroxy‐4Z,7Z,10,12,14,19Z‐docosahexaenoic acid (Protectin sulfido‐conjugates) or 8‐glutathionyl, 7,17‐dihydroxy‐4Z,9, 11,13Z,15E,19Z‐docosahexaenoic acid and 8‐cysteinylglycinyl, 7,17‐dihydroxy‐4Z,9,11,13Z, 15E,19Z‐docosahexaenoic acid (Resolvin sulfido‐conjugates). Each protectin and resolvin sulfido‐conjugate dose dependently (0.1‐10 nM) stimulated human macrophage bacterial phagocytosis, phagolysosomal acidification, and efferocytosis. Together, these results identify 2 novel pathways and provide evidence for structural elucidation of new resolution moduli. These resolvin and protectin conjugates identified in mice and human infected tissues control host responses promoting catabasis.—Dalli, J., Ramon, S., Norris, P. C., Colas, R. A., Serhan, C. N. Novel proresolving and tissue‐regenerative resolvin and protectin sulfido‐conjugated pathways. FASEB J. 29, 2120‐2136 (2015). http://www.fasebj.org

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Dietary fish oil omega‐3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti‐inflammatory effects through unresolved mechanisms. EPA and DHA may reduce arachidonic acid (AA) metabolism and pro‐inflammatory effects by competition and inhibition at multiple levels. Here, we report the effects of AA, EPA, and DHA supplementation on membrane incorporation, phospholipase A2 release, and eicosanoid production in RAW264.7 macrophages. Each PUFA supplemented increased by similar amounts in membrane phospholipids, while half of the increased AA and EPA were elongated to adrenic acid (AdA) and docosapentaenoic acid (DPA), respectively; and were subsequently released by PLA2 at levels comparable to AA. TLR‐4 stimulated COX‐2 AA production did not increase with AA supplementation and was inhibited by 20% and 50% after EPA and DHA supplementation, respectively. ATP stimulated COX‐1 AA production was inhibited to a greater extent by EPA and DHA; 5‐LOX AA metabolites increased 2‐fold with EPA and DHA supplementation, and 5‐LOX metabolized EPA and DHA to a greater extent than COX‐1/COX‐2. Altogether, AA, EPA and DHA supplementation decreased TLR‐4 stimulated AA COX‐2 prostanoid metabolism; increased the purinergic stimulated AA 5‐LOX/COX‐1 ratio; and significantly increased elongated PUFA levels that may be converted to novel mediators.

Specialized pro-resolving mediators (SPM), e.g. Resolvin D1, Protectin D1, Lipoxin A4, and Resolvin E1 have each shown to be active in ocular models reducing inflammation. In general, SPMs have specific agonist functions that stimulate resolution of infection and inflammation in animal disease models. The presence and quantity of SPM in human emotional tears is of interest. Here, utilizing a targeted LC-MS-MS metabololipidomics based approach we document the identification of pro-inflammatory (Prostaglandins and Leukotriene B4) and pro-resolving lipid mediators (D-series Resolvins, Protectin D1, and Lipoxin A4) in human emotional tears from 12 healthy individuals. SPMs from the Maresin family (Maresin 1 and Maresin 2) were not present in these samples. Principal Component Analysis (PCA) revealed gender differences in the production of specific mediators within these tear samples as the SPMs were essentially absent in these female donors. These results indicate that specific SPM signatures are present in human emotional tears at concentrations known to be bioactive. Moreover, they will help to further appreciate the mechanisms of production and action of SPMs in the eye, as well as their physiologic roles in human ocular disease resolution.

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA 4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity. metabolomics | eicosanoids | resolvins | inflammation | metastasis M ore than 80 million aspirin tablets are consumed every year (1). Epidemiologic evidence suggests that the nonsteroidal anti-inflammatory drug (NSAID) aspirin reduces the risk and incidence of cancer and also prolongs survival when administered postdiagnosis (2). While initial studies have focused on colorectal cancers, low-dose aspirin has also demonstrated consistent antitumor activity in other cancers, including lung, breast, prostate, and metastatic cancers (3,4). Studies have also identified survival and chemopreventive benefits of low-dose aspirin following cytotoxic therapy (e.g., radiation, chemotherapy) or surgical tumor resection (5, 6). Compelling evidence of aspirin's anticancer activity stems from patients receiving low-dose aspirin for cardioprevention, in which a substantial fraction (20-30%) benefits from a decrease in cancer incidence (7). In contrast, several studies show that neither nonaspirin NSAIDs nor acetaminophen are associated with a reduced risk of cancer or chemopreventive activity (8,9). While the known anti-inflammatory activity of aspirin offers a generic rationale, the unique antitumor mechanisms of aspirin compared with other NSAIDs remain poorly understood. Importantly, the use of low-dose aspirin in cancer patients is limited by adverse side effects, such as gastrointestinal bleeding and hemorrhagic stroke, that necessitate hospitalization (10).The study of anti-inflammatory mechanisms in cancer has traditionally focused on the suppression of proinflammatory mediators, such as cytokines, eicosanoids, and enzymes (2). Cycloo...

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