Cheng H.Y.Chu J.Limjunyawong N.Chen J.Ye Y.Chen K.H.Koylass N.Sun S.Dong X.Qiu Z.Mahidol University2025-09-142025-09-142025-11-03Journal of Experimental Medicine Vol.222 No.11 (2025)https://repository.li.mahidol.ac.th/handle/123456789/112049The success of phagosome degradation relies on the ability of phagocytes to regulate the maturation of phagosomes. However, its underlying molecular mechanisms remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon Escherichia coli infection in mice. Surprisingly, phagosome degradation also stimulated STING-IRF3-IFN responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation induced the release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages.MedicineImmunology and MicrobiologyArticleSCOPUS10.1084/jem.202503122-s2.0-1050152483181540953840844458