RvD1 accelerates the resolution of inflammation by promoting apoptosis of the recruited macrophages via the ALX/FasL-FasR/caspase-3 signaling pathway

Abstract

The uncontrolled inflammatory response caused by a disorder in inflammation resolution is one of the reasons for acute respiratory distress syndrome (ARDS). The macrophage pool markedly expands when inflammatory monocytes, known as recruited macrophages, migrate from the circulation to the lung. The persistent presence of recruited macrophages leads to chronic inflammation in the resolution phase of inflammation. On the contrary, elimination of the recruited macrophages at the injury site leads to the rapid resolution of inflammation. Resolvin D1 (RvD1) is an endogenous lipid mediator derived from docosahexaenoic acid. Mice were administered RvD1 via the tail vein 3 and 4 days after stimulation with lipopolysaccharide. RvD1 reduced the levels of the inflammatory factors in the lung tissue, promoted the anti-inflammatory M2 phenotype, and enhanced the phagocytic function of recruited macrophages to alleviate acute lung injury. We also found that the number of macrophages was decreased in BAL fluid after treatment with RvD1. RvD1 increased the apoptosis of recruited macrophages partly via the FasL-FasR/caspase-3 signaling pathway, and this effect could be blocked by Boc-2, an ALX/PRP2 inhibitor. Taken together, our findings reinforce the concept of therapeutic targeting leading to the apoptosis of recruited macrophages. Thus, RvD1 may provide a new therapy for the resolution of ARDS.

Enhanced silver nanoparticle-induced pulmonary inflammation in a metabolic syndrome mouse model and resolvin D1 treatment

“…RvD1 treatment increased production of IL-4 and IL-10 earlier in our time course in MetS suggesting an enhancement of anti-inflammatory signaling. Moreover, RvD1 enhances macrophage recruitment, which was observed in our study, and specifically recruits M2-like IL-10 producing macrophages [19,20,59].…”

“…RvD1 is produced via lipoxygenase-mediated metabolism and promotes resolution by activation of G Protein-Coupled Receptor 32 (GPR32) or formyl peptide receptor 2 (ALX/FPR2) receptors [13]. The effectiveness of RvD1 as a treatment option has been investigated in various inflammatory diseases using a variety of models [19][20][21][22][23]. Specifically, RvD1 treatment reduced inflammation and improved lung function following challenges with lipopolysaccharides, cigarette smoke, bacteria, or hyperoxia [21,22,[24][25][26].…”

H3K27 tri-demethylase JMJD3 inhibits macrophage apoptosis by promoting ADORA2A in lipopolysaccharide-induced acute lung injury

“…Lipopolysaccharide (LPS)-stimulated macrophages to promote inflammation and ALI development. The apoptosis of activated macrophages is inhibited in the response to LPS stimulation [2] which aggravates the inflammatory reaction [3]. Conversely, the enhancement of LPSstimulated macrophages' apoptosis relieves acute inflammation [3,4].…”

The role of lung macrophages in acute respiratory distress syndrome

“…MDMs apoptosis promotes inflammation resolution and attenuates pulmonary fibrosis [ 28 , 35 , 67 , 68 ]. After 3–4 days of LPS stimulation in mice, injection of RvD1 (Resolvin D1) via the tail vein promotes the apoptosis of recruited macrophages through the ALX/FasL-FasR/caspase3 signaling pathway, thereby promoting the regression of inflammation [ 67 ].…”

“…MDMs apoptosis promotes inflammation resolution and attenuates pulmonary fibrosis [ 28 , 35 , 67 , 68 ]. After 3–4 days of LPS stimulation in mice, injection of RvD1 (Resolvin D1) via the tail vein promotes the apoptosis of recruited macrophages through the ALX/FasL-FasR/caspase3 signaling pathway, thereby promoting the regression of inflammation [ 67 ]. William et al found that activation of the death receptor Fas leads to depletion of RecAMs but not RAMs, which indicates that apoptosis of RecAMs plays a beneficial role in the processes of resolution of ALI [ 28 ].…”