Resolvin D1 promotes efferocytosis in aging by limiting senescent cell‐induced MerTK cleavage

Abstract

Inflammation‐resolution is mediated by the balance between specialized pro‐resolving mediators (SPMs) like resolvin D1 (RvD1) and pro‐inflammatory factors, like leukotriene B4 (LTB4). A key cellular process of inflammation‐resolution is efferocytosis. Aging is associated with defective inflammation‐resolution and the accumulation of pro‐inflammatory senescent cells (SCs). Therefore, understanding mechanism(s) that underpin this impairment is a critical gap. Here, using a model of hind limb ischemia‐reperfusion (I/R) remote lung injury, we present evidence that aging is associated with heightened inflammation, impaired SPM:LT ratio, defective efferocytosis, and a decrease in MerTK levels in injured lungs. Treatment with RvD1 mitigated I/R lung injury in aging, promoted efferocytosis, and prevented the decrease of MerTK in injured lungs from old mice. Old MerTK cleavage‐resistant mice (MerTKCR) exhibited less neutrophils or polymorpho nuclear cells infiltration and had improved efferocytosis compared with old WT controls. Mechanistically, macrophages that were treated with conditioned media (CM) from senescent cells had increased MerTK cleavage, impaired efferocytosis, and a defective RvD1:LTB4 ratio. Macrophages from MerTKCR mice were resistant to CM‐induced efferocytosis defects and had an improved RvD1:LTB4 ratio. RvD1‐stimulated macrophages prevented CM‐induced MerTK cleavage and promoted efferocytosis. Together, these data suggest a new mechanism and a potential therapy to promote inflammation‐resolution and efferocytosis in aging.

Role of Apoptotic Cell Clearance in Pneumonia and Inflammatory Lung Disease

“…Application of exogenous RvD1 reduced both bacterial growth and neutrophil infiltration, in both acute and long-term murine models of pneumonia [ 173 ]. While further studies of the therapeutic potential of resolvins are required in humans, these findings suggest that RvD1 may be a plausible therapeutic target in treating bacterial pneumonia due to its role in inhibiting inflammation and enhancing tissue healing in murine lung models [ 277 , 278 , 279 , 280 ]. To date, no human clinical trials with resolvins have been reported, but these compounds are well tolerated in mice [ 281 ].…”

Resolvins: Potent Pain Inhibiting Lipid Mediators via Transient Receptor Potential Regulation

“…Resolution of acute inflammation was introduced as a passive process following disappearance of the chemoattractant and other chemical mediators, but Dr. Serhan’s group uncovered endogenous lipid mediators in inflammatory exudate: resolvins, protectins, and maresins ( Serhan et al, 2002 ; Serhan, 2014 ). These pro-resolving lipid mediators are often referred to as specialized pro-resolving mediators (SPMs) because they stimulate efferocytosis of polymorphonuclear leukocytes (PMNs) to facilitate complete removal of pathogens, recruit macrophages, attenuate activated neutrophil through NF-κB inhibition, and initiate the resolution phase of acute inflammation ( Flower and Perretti, 2005 ; Lee et al, 2013 ; Francos-Quijorna et al, 2017 ; Yurdagul et al, 2017 ; Rymut et al, 2020 ).…”

Exploiting oxidized lipids and the lipid‐binding GPCRs against cardiometabolic diseases

“…Impairment in resolution of vascular inflammation contributes for the pathogenesis of atherosclerosis (Bäck, Yurdagul, Tabas, Öörni, & Kovanen, 2019). In this context, RvD1 can also exert a protective effect against atherosclerosis, especially by stimulating efferocytosis, which consists of the clearance of apoptotic cells by macrophages (Rymut et al, 2020). The accumulation of necrotic cells (NCs) is also critical for the progression of the atheroma plaque, especially due to its inefficient engulfment by macrophages because of their increased surface expression of a well‐known “don't eat me” signal, CD47 (Gerlach et al, 2020).…”