Cheng Henry Yi, Chu Jiachen, Limjunyawong Nathachit, Chen Jianan, Ye Yingzhi, Chen Kevin Hong, Koylass Nicholas, Sun Shuying, Dong Xinzhong, Qiu Zhaozhu
Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Exp Med. 2025 Nov 3;222(11). doi: 10.1084/jem.20250312. Epub 2025 Aug 22.
The 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.
吞噬体降解的成功依赖于吞噬细胞调节吞噬体成熟的能力。然而，其潜在的分子机制仍知之甚少。在这里，我们确定质子激活氯（PAC）通道是吞噬体成熟的关键负调节因子。PAC缺失增强了吞噬体酸化和蛋白酶活性，导致小鼠感染大肠杆菌后，大型腹膜巨噬细胞（LPMs）中的细菌杀伤增加。令人惊讶的是，吞噬体降解还刺激了LPMs中的STING-IRF3-IFN反应和炎性小体激活，在PAC缺失时两者均增强。炎性小体激活增加诱导了裂解的gasdermin D的释放，其定位于腹膜中细菌的表面，并进一步促进了对细菌的杀伤。最后, PAC缺陷的LPMs增强的细菌清除减少了促炎免疫细胞浸润和腹膜炎症，从而提高了小鼠的存活率。因此，我们的研究为吞噬体成熟的分子机制以及腹膜巨噬细胞中吞噬体介导的细菌降解后宿主防御反应的动力学提供了新的见解。
