Enhancement of autophagy in macrophages via the p120-catenin-mediated mTOR signaling pathway

Abstract

Abstract Autophagy serves as a critical regulator of immune responses in sepsis. Macrophages are vital constituents of both innate and adaptive immunity. In this study, we delved into the intricate role of p120-catenin (p120) in orchestrating autophagy in macrophages, particularly in their response to endotoxin stimulation. Depletion of p120 effectively suppressed lipopolysaccharide (LPS)-induced autophagy in both J774A.1 macrophages and murine bone BMDMs. LPS not only elevated the interaction between p120 and LC3I/II, but also facilitated the binding of p120 with mTOR. The absence of p120 led to the inhibition of LPS-induced dissociation between mTOR and ULK-1, consequently promoting the phosphorylation of ULK-1 upon LPS stimulation in macrophages. p120 depletion also heightened LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3. Notably, a decrease in apoptosis observed in macrophages overexpressing p120 upon LPS stimulation was reversed by inhibiting autophagy. Additionally, the ablation of p120 accentuated LPS-induced alveolar macrophage apoptosis in LPS-challenged mice. Collectively, our findings strongly suggest that p120 plays a pivotal role in fostering autophagy while concurrently hindering apoptosis in macrophages, achieved through modulation of the mTOR/ULK-1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders.