P120 catenin enhances macrophage efferocytosis and facilitates resolution of lung inflammatory injury

Abstract

Abstract Efficient clearance of apoptotic neutrophils (PMNs) (efferocytosis) after sepsis plays a crucial role in facilitating tissue repair, resolving inflammation, and maintaining immune system balance. Here, we identified p120 catenin (p120) as a pivotal regulator in efferocytosis and subsequent recovery from inflammatory lung injury. We found that specific macrophage p120 deletion had a profound delay in the resolution of PMN infiltration, extracellular protein accumulation, and lung edema and injury following LPS challenge. p120 deletion increased the levels of TNF-α and IL-6, and reduced the levels of TGF-β1 and IL-10. Depletion of p120 also led to a marked decrease in the phagocytosis of apoptotic PMNs by macrophages. The number of p120-depleted alveolar macrophages containing apoptotic PMNs in bronchoalveolar lavage fluid was significantly lower. p120 deficiency caused a reduction in the expression of key efferocytosis-related molecules, namely AXL and CD36. p120-depleted macrophages exhibited a shift in polarization towards the M1 phenotype. Apoptotic cells triggered the association and co-localization of p120 and PPAR, and p120 deletion decreased the activity of PPARgamma in response to apoptotic PMNs. Inhibition of PPAR abolished p120-mediated efferocytosis and the resolution of lung inflammation. These findings underscore the critical role of p120 in facilitating the resolution of lung inflammation through modulation of macrophage polarization and PPAR signaling pathway.