Molecular Circuits of Resolution: Formation and Actions of Resolvins and Protectins

Abstract

The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including Ψmax, the maximal neutrophil numbers that are present during the inflammatory response; Tmax, the time when Ψmax occurs; and the resolution interval (Ri) from Tmax to T50 when neutrophil numbers reach half Ψmax. The onset of resolution was at ∼12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10,17S-docosatriene was generated during the Ri. Administration of aspirin-triggered lipoxin A4 analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A4 analog reduced Ψmax, resolvin E1 decreased both Ψmax and Tmax, whereas 10,17S-docosatriene reduced Ψmax, Tmax, and shortened Ri. Also, aspirin-triggered lipoxin A4 analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20–50% inhibition), whereas resolvin E1 and 10,17S-docosatriene’s inhibitory actions were maximal at 12 h (30–80% inhibition). Moreover, aspirin-triggered lipoxin A4 analog evoked release of the antiphlogistic cytokine TGF-β. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin E1 and 10,17S-docosatriene) to promote resolution.

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

“…Both E-series and D-series resolvins control cytokine expression in a zymosan-induced peritonitis and cecal ligation and puncture model in mice that causes polymicrobial sepsis (24,52,53). These actions of resolvins were further supported by results of in vitro and in vivo studies of the regulation of cytokine production by E series resolvins, wherein RvE1 reduced TNF-α, IL-1β, and IL-6, demonstrating its nonphlogistic actions during inflammation resolution, increasing microbial containment and clearance.…”

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…Membrane fluidity and the role of cytokines have been reviewed in Refs. [8,11,120,152]. derived from the n-6 PUFA AA and it is the major prostaglandin in bone.…”

“…Lipoxygenase (LOX) generated lipid mediators (resolvins, lipoxins, protectins and docosanoids) have both anti-inflammatory and pro-resolving activities [120,121]. Both resolvins and lipoxins inhibit inflammation-induced bone resorption and may therefore provide a mechanism by which the n-3 PUFAs protect against bone loss.…”

The impact of an omega-3 fatty acid rich lipid emulsion on fatty acid profiles in critically ill septic patients

“…However, it has also been shown that DHA may have a stronger affinity for raft regions and therefore may have a more influential effect on lipid rafts leading to an increased fluidity and reduced order 30,31 . Both EPA and DHA give rise to resolvins that are now recognised as significant lipid mediators involved in resolution of inflammation and in immunomodulation [32][33][34][35][36][37] .…”