p120-catenin enhances macrophage efferocytosis, resolving inflammatory lung injury in endotoxin-challenged mice

Defective resolution of inflammation following sepsis contributes significantly to persistent immune dysfunction, morbidity, and mortality globally. Efficient clearance of apoptotic polymorphonuclear neutrophils (PMNs) by macrophages, a process termed efferocytosis, is crucial for resolving inflammation, facilitating tissue repair, and restoring immune homeostasis. However, the precise molecular mechanisms governing this vital process remain poorly understood, representing a significant gap in therapeutic strategies for inflammatory lung injury.

Researchers investigated the role of p120-catenin in inflammatory lung injury using alveolar macrophage-depleted mice challenged with endotoxin. They performed intratracheal instillation of p120-deficient macrophages compared to control macrophages. Key endpoints included the resolution of PMN infiltration, protein exudation, lung edema, and overall lung injury. Cytokine levels (TNF-α, IL-6, TGF-β, IL-10) were measured in bronchoalveolar lavage fluid, and macrophage phagocytosis of apoptotic PMNs was assessed in cultured macrophages. Mechanistic studies involved evaluating efferocytic receptor expression (CD36, Axl) and macrophage polarization, alongside investigating the association of p120 with PPARγ activity.

Intratracheal instillation of p120-deficient macrophages significantly delayed the resolution of PMN infiltration, protein exudation, lung edema, and injury compared to control macrophages in endotoxin-challenged mice. These detrimental changes were accompanied by increased levels of pro-inflammatory TNF-α and IL-6, while anti-inflammatory TGF-β and IL-10 levels decreased. The number of macrophages containing apoptotic PMNs in bronchoalveolar lavage fluid was notably reduced. 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).