p120-catenin enhances macrophage efferocytosis and facilitates resolution of lung inflammatory injury

Abstract

Abstract Defective resolution of inflammation following sepsis contributes to persistent immune dysfunction and increased morbidity and mortality worldwide. Efficient clearance of apoptotic polymorphonuclear neutrophils (PMNs) by macrophages, a process known as efferocytosis, is essential for resolving inflammation, promoting tissue repair, and restoring immune homeostasis; however, the molecular mechanisms governing this process remain poorly understood. Here, we identify p120-catenin (p120) as a critical regulator of efferocytosis that promotes the resolution of inflammatory lung injury. In alveolar macrophage–depleted mice challenged with endotoxin, intratracheal instillation of p120-deficient macrophages delayed the resolution of PMN infiltration, protein exudation, and lung edema and injury compared with control macrophages. These changes were accompanied by increased levels of TNF-α and IL-6, decreased levels of TGF-β and IL-10, and a reduced number of macrophages containing apoptotic PMNs in bronchoalveolar lavage fluid. p120 depletion also markedly reduced the phagocytosis of apoptotic PMNs by cultured macrophages. Mechanistically, p120 deficiency decreased the expression of the efferocytic receptors CD36 and Axl and shifted macrophage polarization toward a pro-inflammatory M1 phenotype. Furthermore, apoptotic cells induced the association and co-localization of p120 with peroxisome proliferator-activated receptor-γ (PPARγ), whereas p120 deletion markedly reduced PPARγ activity in response to apoptotic PMNs. Pharmacologic inhibition of PPARγ abolished p120-mediated macrophage efferocytosis and the resolution of lung inflammation. Collectively, these findings establish a central role for p120 in macrophage efferocytosis and inflammatory resolution and suggest that targeting macrophage p120 may represent a novel therapeutic strategy to promote recovery from inflammatory lung injury.