Enhancement of Autophagy in Macrophages via the p120-Catenin-Mediated mTOR Signaling Pathway.

Autor:	Kanmani S; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL., Song XM; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL.; Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Wuchang, Hubei Province, China., Kanmani P; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL., Wu XJ; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL.; Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Wuchang, Hubei Province, China., Tan XD; Department Pediatrics, University of Illinois College of Medicine, Chicago, IL., Liu J; Department of Surgery/Cancer Center, University of Illinois College of Medicine, Chicago, IL., Wang JP; Departments of Statistics and Data Science, Northwestern University, Evanston, IL; and., Minshall RD; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL.; Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL., Hu G; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL.; Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2024 Dec 01; Vol. 213 (11), pp. 1666-1675.
DOI:	10.4049/jimmunol.2400189
Abstrakt:	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 in response to endotoxin stimulation. Depletion of p120 effectively suppressed LPS-induced autophagy in both J774A.1 macrophages and murine bone marrow-derived macrophages. LPS not only elevated the interaction between p120 and L chain 3 (LC3) I/II but also facilitated the association of p120 with mammalian target of rapamycin (mTOR). p120 depletion in macrophages by small interfering RNA reduced LPS-induced dissociation of mTOR and Unc-51-like kinase 1 (ULK1), leading to an increase in the phosphorylation of ULK1. p120 depletion also enhanced LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3, 7-aminoactinomycin D staining, and TUNEL assay. Notably, inhibiting autophagy reversed the decrease in apoptosis caused by LPS stimulation in macrophages overexpressing p120. Additionally, the ablation of p120 inhibited autophagy and accentuated apoptosis in alveolar macrophages 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/ULK1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders. (Copyright © 2024 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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