Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

Abstract

Resolution of inflammation is a finely regulated process mediated by specialized pro-resolving lipid mediators (SPMs) including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. Here, we report that the D-series resolvins Resolvin D1 and Resolvin D2 and Maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8 T cells and CD4 T-helper (TH) 1 and TH17 cells, but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4 T-cell differentiation into TH1 and TH17 by downregulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3+ regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2−/−) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild type mice. Additionally, either DHA supplementation in Elovl2−/− mice or in vivo administration of Resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation.

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

“…Sex differences in resolution mechanism in inflammation are also observed in humans, where healthy females on skin challenge produce higher levels of D-series resolvins than males that is associated with accelerated resolution (Rathod et al, 2016). These results suggest that specific SPM may prevent autoimmunity (Gao et al, 2015; Rathod et al, 2016) and link resolution to T cell responses (Chiurchiu et al, 2016). In obese women, supplementation with n-3 PUFA increases systemic resolvins and upregulation of resolvin receptors (Polus et al, 2016), suggesting that, in humans, failed resolution can be rescued.…”

“…The Phase II trial controlling inflammation in the eye with topical drops (Business Wire, 2009) was based on the physiologic roles (Gronert, 2010; Li et al, 2010; Erdinest et al, 2014) of SPM such as resolvins and lipoxins in the eye (Li et al, 2013; Hodges et al, 2016; Dartt et al, 2011; Cortina and Bazan, 2011) and apparent gender differences, where females display delayed wound healing of cornea tissue and reduced 15-LOX-derived SPM such as lipoxin A 4 (Gao et al, 2015; Wang et al, 2012). Since 15- R/S -methyl lipoxin A 4 , an analog of the aspirin-triggered form of lipoxin A 4 , one of the first stop signals and pro-resolving mediators, is effective in infantile eczema in a double-blind, placebo-controlled study randomized at two different centers (Wu et al, 2013), and LXA 4 , resolvin D1, RvD2 and maresin 1 act on T-cell responses (Chiurchiu et al, 2016; Gao et al, 2015), it is likely that SPM have physiologic roles in human skin and barrier functions that remain to be studied, and their functions extend from the resolution phase into the adaptive immune response (Ramon et al, 2012). It is hoped that results from these studies can open up new directions for treatment of a wide range of human diseases by controlling the resolution and endogenous catabasis mechanisms of the inflammatory response via resolution and regeneration agonists.…”

Monocyte-Macrophages and T Cells in Atherosclerosis

“…In a lung model of self-limited allergic inflammation, the SPM maresin 1 has been shown to induce Treg cells, which then inhibited type 2 innate lymphoid cells. A recent in vitro study has shown that SPMs can block differentiation of naïve human T cells to Th1 and Th17 cell effectors, block Teff cell inflammatory cytokine production including IFN-γ, and induce Treg cells (Chiurchiu et al, 2016). These in vitro findings are supported by studies in Elovl2 −/− mice, which are defective in SPM production and shown to have more Th1 and Th17 cells in lymphoid tissues and less Treg cells than control mice.…”

Age-Associated DNA Methylation Changes in Naive CD4 + T Cells Suggest an Evolving Autoimmune Epigenotype in Aging T Cells

“…We observed a second CpG site associated with ELOVL2 (cg24724428) with a slightly lower, but significant association with age (Pearson coefficient = 0.72). A recent study of Elovl2 (-/-) mice has shown increased production of the inflammatory cytokines IFN-γ and IL-17, a sign of increased Th1 and Th17 activity, and a reduction in the number of Foxp3+ T reg cells compared with wild-type mice [67]. As hypermethylation is generally associated with transcriptional silencing, progressive age-dependent hypermethylation of ELOVL2 in naive CD4 + T cells might suggest a proinflammatory T-cell epigenotype with age.…”