Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli–driven acute inflammation

Abstract

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli–triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution

“…Additionally, our functional findings were accompanied by an increased expression of several important proresolving receptors (GPR32, ChemR23, ALX, and GPR18), strengthening our line of argumentation. These receptors have just recently been shown to be involved in inflammation resolution in a human skin blister model (55). Ultimately, we monitored important CYP, 15-LOX, and COX pathway markers under treatment of human MΦ with zyA, with and without SH42.…”

“…The aforementioned findings might lead to novel treatment opportunities, as polymorphisms in the 15-LOX pathway have been linked to the development of asthma, arthritis, and atherosclerosis in humans. Products of this pathway (MaR1 and LXA 4 ) have been described in a human skin blister model (55,56).…”

Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions

“…MaR1 is produced in humans (7,(15)(16)(17)(18)(19), and its defining physiologic functions include limiting PMN infiltration in murine peritonitis, enhancing human MΦ uptake of apoptotic PMNs (16), the hallmarks of proresolving mechanisms. By controlling inflammation after surgical tissue injury, MaR1 accelerates planaria regeneration (12).…”

Pro-resolving lipid mediators in vascular disease

“…Subsequent studies have demonstrated a lipid mediator "class switch" in the biochemical transition from inflammation to resolution, wherein early proinflammatory prostaglandins and leukotrienes are replaced by SPMs in exudates. The mechanisms of this shift in eicosanoid profile involve temporal changes in the expression, localization, and activity of key cellular enzymes such as 5-and 15-lipoxygenases (LOXs) (10)(11)(12). Once available, SPMs coordinate crosstalk between leukocytes and local cell populations, promoting an M1-M2 phenotypic transition in macrophages that is central to tissue repair (13).…”

“…Once available, SPMs coordinate crosstalk between leukocytes and local cell populations, promoting an M1-M2 phenotypic transition in macrophages that is central to tissue repair (13). SPMs further promote resolution by positive-feedback effects on LOX activity and SPM receptor expression in leukocytes (11,12,14). Translation of these concepts into therapies for complex human diseases is the current challenge faced by investigators in this exciting, evolving field.…”