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Infections arise when the host response is overwhelmed by pathogens leading to organ dysfunction. In some instances patients progress to more severe conditions, including septic shock, that are associated with increased mortality. Current strategies in treating infections aim at either blocking inflammation using inhibitors to pro-inflammatory molecules and/or inhibiting bacterial growth using antibiotics. These approaches find their origins in studies conducted by Joseph Lister who demonstrated that applying carbolic acid to wounds promoted wound healing without suppuration, reducing both the necessity of amputation and mortality. While this approach is still applicable to certain infections, inhibition of the immune response is also associated with increased mortality, especially in septic patients. In many instances sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections. This, together with a rise in resistance to many frontline antibiotics, has prompted a search for alternative ways to treat infections. Recent studies investigating processes engaged by the host response during self-resolving infections identified a novel group of mediators, termed as specialized pro-resolving mediators (SPM). These molecules, produced via the enzymatic conversion of essential fatty acids, actively reprogram the immune response to promote clearance of invading pathogens, and counter-regulate the production of inflammation-initiating molecules. Furthermore, recent studies also demonstrate that these mediators promote tissue repair and regeneration, essential processes in the re-establishment of barrier and prevention of re-infection. The scope of the present review is to discuss the evidence underpinning the endogenous protective roles of these novel mediators, as well as the evidence demonstrating that dysregulation in their production and actions contribute to disease pathogenesis in infections. This review will also discuss the potential of resolution pharmacology-based approaches in developing new therapeutics for combatting infections that do not interfere with the immune response. ; This work was supported by funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (Grant number: 677542), a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number: 107613/Z/15/Z) and the Barts Charity (Grant number: MGU0343).

"This is the pre-peer reviewed version of the following article: Jesmond, D. and S. C. N "Identification and structure elucidation of the proresolving mediators provides novel leads for resolution pharmacology." British Journal of Pharmacology 0(ja)., which has been published in final form at https://doi.org/10.1111/bph.14336. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions." ; Studies reviewed here from the authors' laboratories were supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number: 107613/Z/15/Z) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant number: 677542) to JD. Studies reviewed from the CN Serhan laboratories were supported by National Institutes of Health (grant numbers R01GM38765 and P01GM095467).

Understanding mechanisms that control immunity is central in the quest to gain insights into the etiopathology of many of the diseases that afflict modern societies. New results implicate the nervous system as a central player in controlling many aspects of both the innate and adaptive arms of the immune response. Furthermore it is now well appreciated that a novel group of autacoids termed as specialized proresolving mediators, which are enzymatically produced from essential fatty acids, orchestrate the immune response promoting the termination of inflammation as well as tissue repair and regeneration. The present brief review discusses evidence for the crosstalk between the nervous system and leukocytes in regulating SPM production. We will also discuss the impact that this has on controlling tissue resolution tone and the resolution of both infectious and sterile inflammation. ; Sir Henry DaleFellowship jointly funded by the Wellcome Trust and the Royal Society(Grant number: 107613/Z/15/Z), the European Research Council (ERC)under the European Union's Horizon 2020 research and innovationprogramme (Grant number: 677542) and the Barts Charity (Grant number:MGU0343) to JD as well as National Institutes of Health (grant numbersR01GM38765 and P01GM095467) to CN

Macrophages are central in coordinating the host response to both sterile and infective insults. Clearance of apoptotic cells and cellular debris is a key biological action preformed by macrophages that paves the way to the resolution of local inflammation, repair and regeneration of damaged tissues, and re-establishment of function. The essential fatty acid-derived autacoids termed specialized pro-resolving mediators (SPM) play central roles in promoting these processes. In the present article, we will review the role of microvesicles in controlling macrophage efferocytosis and SPM production. We will also discuss the role of both apoptotic cells and microvesicles in providing substrate for transcellular biosynthesis of several SPM families during efferocyotsis. In addition, this article will discuss the biological actions of the recently uncovered macrophage-derived SPM termed maresins. These mediators are produced via 14-lipoxygenation of docosahexaenoic acid that is either enzymatically converted to mediators carrying two hydroxyl groups or to autacoids that are peptide-lipid conjugates, coined maresin conjugates in tissue regeneration. The formation of these mediators is temporally regulated during acute self-limited infectious-inflammation where they promote the uptake and clearance of apoptotic cells, regulate several aspects of the tissue repair and regeneration, and display potent anti-nociceptive actions. ; Studies in the authors' laboratories were supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number: 107613/Z/15/Z), funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant number: 677542), the Barts Charity (Grant number: MGU0343) to JD, and National Institutes of Health (grant numbers R01GM38765 and P01GM095467) to CNS.

The Norwegian Research Council is gratefully acknowledged for generous funding to T.V.H (KOSK 197708, KOSK II 207053, BIOTEK2021 224811, FRIPRO-FRINATEK 230470). T.V.H. is also thankful for a Leiv Eriksson travel grant from The Norwegian Research Council enabling a sabbatical period with Professor Charles N. Serhan. J.D. received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant no: 677542) and the Barts Charity (grant no: MGU0343). J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z).

This work was supported by funding from the European Research Council (ERC) under the European Union's Horizon 2020 research (No 677542) and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z both to JD). L.V.N is supported by a Career Development Fellowship 19909 funded by Arthritis Research UK

N-3 docosapentaenoic acid–derived resolvin D5 (RvD5n-3 DPA) is diurnally regulated in peripheral blood and exerts tissue-protective actions during inflammatory arthritis. Here, using an orphan GPCR screening approach coupled with functional readouts, we investigated the receptor(s) involved in mediating the leukocyte-directed actions of RvD5n-3 DPA and identified GPR101 as the top candidate. RvD5n-3 DPA bound to GPR101 with high selectivity and stereospecificity, as demonstrated by a calculated KD of approximately 6.9 nM. In macrophages, GPR101 knockdown limited the ability of RvD5n-3 DPA to upregulate cyclic adenosine monophosphate, phagocytosis of bacteria, and efferocytosis. Inhibition of this receptor in mouse and human leukocytes abrogated the pro-resolving actions of RvD5n-3 DPA, including the regulation of bacterial phagocytosis in neutrophils. Knockdown of the receptor in vivo reversed the protective actions of RvD5n-3 DPA in limiting joint and gut inflammation during inflammatory arthritis. Administration of RvD5n-3 DPA during E. coli–initiated inflammation regulated neutrophil trafficking to the site of inflammation, increased bacterial phagocytosis by neutrophils and macrophages, and accelerated the resolution of infectious inflammation. These in vivo protective actions of RvD5n-3 DPA were limited when Gpr101 was knocked down. Together, our findings demonstrate a fundamental role for GPR101 in mediating the leukocyte-directed actions of RvD5n-3 DPA. ; This work was supported by funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Program (grant 677542, to JD); a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z); the Barts Charity (grant MGU0343, to JD); a Marie Sklodowska Curie IF Fellowship under the European Union's Horizon 2020 Research and Innovation Program (grant 746183); and the Barts Charity (grant MGU0439, to MBF).

RATIONALE: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response. OBJECTIVE: Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation. METHODS AND RESULTS: Using lipid mediator profiling and healthy volunteers, we found that plasma concentrations of n-3 docosapentaenoic acid-derived D-series resolvins (RvDn-3 DPA) were regulated in a diurnal manner. The production and regulation of these mediators was markedly altered in patients at risk of myocardial infarct. These changes were associated with decreased 5-lipoxygenase expression and activity, as well as increased systemic adenosine concentrations. We also found a significant negative correlation between plasma RvDn-3 DPA and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvDn-3 DPA with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5n-3 DPA to ApoE-/- (apolipoprotein E deficient) mice significantly reduced platelet-leukocyte aggregates, vascular thromboxane B2 concentrations, and aortic lesions. CONCLUSIONS: These results demonstrate that peripheral blood RvDn-3 DPA are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease. ; Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number: 107613/Z/15/Z), ; European Research Council under the European Union's Horizon 2020 research and innovation program (grant number: 677542), ; Barts Charity (grant number: MGU0343 ; Medical Research Council Advance Course Masters (grant number: MR/J015741/1) ; Science Foundation Ireland Starting Investigator Research Grant 13/SIRG/2130 ; Wellcome Trust grant 101604/Z/13/Z

S.G.D. is a recipient of an Oxford UCB Prize Fellowship in Biomedical Research and also received funding from Arthritis Research UK (grant no: 20506). Arthritis Research UK also supported UO (program grant 20522). J.D. received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant no: 677542) and the Barts Charity (grant no: MGU0343). J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z). Research at NDORMS, University of Oxford is supported through the National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Centre (BRC).

Rationale: Specialized pro-resolving mediators (SPM—lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation. Of note, the mechanism(s) activated by these supplements in exerting their protective actions remain poorly understood. Objective: Given that essential fatty acids are precursors in the biosynthesises of SPM, the aim of the present study was to establish the relationship between supplementation and peripheral SPM concentrations. We also investigated the relationship between changes in plasma SPM concentrations and peripheral blood platelet and leukocyte responses. Methods and Results: Healthy volunteers were enrolled in a double-blinded, placebo-controlled, crossover study, and peripheral blood was collected at baseline, 2, 4, 6, and 24 hours post administration of placebo or one of 3 doses of an enriched marine oil supplement. Assessment of plasma SPM concentrations using lipid mediator profiling demonstrated a time- and dose-dependent increase in peripheral blood SPM concentration. Supplementation also led to a regulation of peripheral blood cell responses. Here we found a dose-dependent increase in neutrophil and monocyte phagocytosis of bacteria and a decrease in the diurnal activation of leukocytes and platelets, as measured by a reduction in adhesion molecule expression. In addition, transcriptomic analysis of peripheral blood cells demonstrated a marked change in transcript levels of immune and metabolic genes 24 hours post supplementation when compared with placebo. Conclusions: Together, these findings demonstrate that supplementation with an enriched marine oil leads to an increase in peripheral blood SPM concentrations and reprograms peripheral blood cells, indicating a role for SPM in mediating the immune-directed actions of this supplement. ; This work was supported by funding from a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 107613/Z/15/Z), funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant number: 677542) and the Barts Charity (Grant MGU0343) to J. Dalli, as well as funding from Metagenics Inc.

The School of Pharmacy, University of Oslo is gratefully acknowledged for a Ph.D. scholarship to K.G.P. The Norwegian Research Council (FRIPRO/FRINATEK 230470) is gratefully acknowledged for funding to T.V.H. J.D. received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant no. 677542) and the Barts Charity (grant no. MGU0343). J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant no. 107613/Z/15/Z). This work is also supported by a Wellcome Trust Infrastructure (grant no. 101604/Z/13/Z).

Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL-1β-stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon-derived stromal cells, 15-epi-Lipoxin A4 (15-epi-LXA4) or maresin (MaR)-1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL-1β treatment induced profound prostaglandin E2 release in AR compared with AT cells. Incubation of IL-1β treated AT and AR tendon-derived stromal cells in 15-epi-LXA4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up-regulated the proresolving receptor ALX compared with vehicle-treated cells. Incubation in 15-epi-LXA4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)-1, IL-6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c-Jun N-terminal kinase 1/2/3, Lyn, STAT-3, and STAT-6 phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15-epi-LXA4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.-Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture. ; European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant 677542 ; Barts Charity (Grant MGU0343) ; Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 107613/Z/15/Z)

Cusanuswerk, who supported D.F. with a stipend. J.D. is funded by European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant no: 677542) and the Barts Charity (grant no: MGU0343) to J.D. J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z).

BACKGROUND: Termination of acute inflammation is an active process orchestrated by lipid mediators (LM) derived from polyunsaturated fatty acids, referred to as specialized pro-resolving mediators (SPM). These mediators also provide novel therapeutic opportunities for treating inflammatory disease. However, the regulation of these molecules following acute myocardial infarction (MI) remains of interest. METHODS: In this prospective observational study we aimed to profile plasma levels of SPMs in ST-elevation MI (STEMI) patients during the first week following MI. Plasma LM concentrations were measured in patients with STEMI (n = 15) at three time points and compared with stable coronary artery disease (CAD; n = 10) and healthy controls (n = 10). FINDINGS: Our main findings were: (i) Immediately after onset of MI and before peak troponin T levels, STEMI patients had markedly increased levels of SPMs as compared with healthy controls and stable CAD patients, with levels of these mediators declining during follow-up. (ii) The increase in SPMs primarily reflected an increase in docosapentaenoic acid- and docosahexaenoic acid-derived protectins. (iii) Several individual protectins were correlated with the rapid increase in neutrophil counts, but not with CRP. (iv) A shift in 5-LOX activity from the leukotriene B4 pathway to the pro-resolving RvTs was observed. INTERPRETATION: The temporal regulation of SPMs indicates that resolution mechanisms are activated early during STEMI as part of an endogenous mechanism to initiate repair. Thus strategies to boost the activity and/or efficacy of these endogenous mechanisms may represent novel therapeutic opportunities for treatment of patients with MI. FUND: This work was supported by grants from the South-Eastern Norwegian regional health authority, the European Research Council under the European Union's Horizon 2020 research and innovation program, a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society, and the Barts Charity. ; South-Eastern Norwegian regional health authority (Helse Sør-Øst RHF) (Grant 2011101). ; Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 1047613/Z/15/Z) ; European Union's Horizon 2020 research and innovation programme (grant no: 677542) ; Barts Charity (Grant MGU0343)

This is a pre-copyedited, author-produced version of an article accepted for publication in Brain: A Journal of Neurology following peer review. The version of record Frigerio, F., et al. (2018). "n-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis." Brain: awy247-awy247. is available online at: xxxxxxx https://doi.org/10.1093/brain/awy247 ; Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues. ; F.F. was a recipient of a fellowship from UCB Biopharma. This work was supported by European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n. 602102 (EPITARGET to A.V., M.C.W., E.A.V., E.A.), Citizen United for Research in Epilepsy (CURE) (A.V.), the Epilepsy Research UK (M.C.W.), and in part by NIH grants RO1 NS086423 and RO1NS039587 (M.P.). This work was also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number: 107613/Z/15/Z), funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant number: 677542), and the Barts Charity (Grant number: MGU0343). The Norwegian Research Council is acknowledged for funding to T.V.H. (FRIPROFRINATEK 230407).