Special pro-resolving mediator (SPM) actions in regulating gastro-intestinal inflammation and gut mucosal immune responses

Abstract

Surfaces covered by epithelial cells, termed mucosal surfaces, serve special functions as selectively permeable barriers that partition the host and the outside world. Given its close association to microbial antigens, the intestinal mucosa has evolved creative mechanisms to maintain homeostasis, to prevent excessive inflammatory responses, and to promote rapid and full inflammatory resolution. In recent years, an active role for the epithelium has been attributed to the local generation of specialized pro-resolving mediators (SPMs) in the maintenance of immunological homeostasis. In this brief review, we highlight evidence that the epithelium actively contributes to coordination and resolution of inflammation, principally through the generation of SPMs. These autacoids are derived from omega-6 and omega-3 polyunsaturated fatty acids. Acting through widely expressed G-protein coupled receptors, SPMs are implicated in the resolution of acute inflammation that manifests specific, epithelial-directed actions focused on mucosal-homeostasis, including regulation of leukocyte trafficking, the generation of antimicrobial peptides, the dampening of endotoxin signaling, and the attenuation of mucosal cytokine responses.

Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution

“…In addition, and in contrast to what was observed after 2 days of treatment, IL‐1β and IL‐6 cytokine release by colonic explant cultures from the MNC‐treated group was now reduced in comparison to the DSS‐control (Figure B). Since eosinophils, Th2 cells and alternatively activated Mφs are actively associated with the resolution phase of acute inflammation, and considering the higher numbers of these cells found in the cLP of MNC‐treated mice, we evaluated the expression of Alox15 , which encodes for the enzyme 12/15‐lipoxygenase, involved in the synthesis of pro‐resolving lipid mediators (Wang and Colgan, ). Interestingly, Alox15 expression was significantly up‐regulated in the colonic tissue of the MNC‐treated group compared to the DSS‐control (Figure C).…”

“…Alternative therapeutic strategies that exploit counter‐regulatory pathways, such as parasites used to skew mucosal immune responses and favour barrier protection, involve alternatively activated macrophages, eosinophils, Th2 cells and Tregs (Smith et al ., ; Hunter et al ., ; Gause et al ., ; Driss et al ., ). These cells play a key role in the resolution of intestinal inflammation, for example, by producing anti‐inflammatory lipid mediators that activate this process (Sherman and Kalman, ; Wang and Colgan, ). Correlating with these immune changes, Alox15 was up‐regulated in the MNC‐ treated group, suggesting the initiation of the resolution phase.…”

Formyl peptide receptors in the mucosal immune system

“…FPR2, which has a lower affinity for formylated peptides than FPR1, recognizes diverse ligands 2 . FPR2 is a specific target receptor for various endogenous molecules, such as antimicrobial peptides (AMPs) and specialized pro-resolving mediators (SPMs) 22 , 26 – 28 . The expression and distribution of FPR2 are quite similar to those of FPR1, from immune cells such as neutrophils to endothelial and epithelial cells 2 .…”

“…The mucosal system maintains homeostasis by producing SPMs, including lipoxins, resolvins, and prostaglandins 28 . FPR2 is a receptor for lipoxin A4 (LXA4) and resolvin D1 (RvD1) and mediates their intestinal protective effects.…”

Resolvins resolve to heal mucosal wounds

“…SPMs have evolved to be synthesized locally and act locally within tissue sites (14). For this reason, strategies to lengthen their half-life and stability in tissues would be welcome.…”