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It is previously reported that TMEM16F, a calcium\u2010activated lipid scramblase expressed in various immune cell types including T cells and neutrophils, is critical for the control of infection by bacterium <jats:italic>Listeria monocytogenes<\/jats:italic> (<jats:italic>Lm<\/jats:italic>) in vivo. This function correlated with the capacity of TMEM16F to repair the plasma membrane (PM) damage induced in T cells in vitro, by the <jats:italic>Lm<\/jats:italic> toxin listeriolysin O (LLO). However, whether the protective effect of TMEM16F on <jats:italic>Lm<\/jats:italic> infection in vivo is mediated by an impact in T cells, or in other cell types, is not determined. Herein, the immune cell types and mechanisms implicated in the protective effect of TMEM16F against <jats:italic>Lm<\/jats:italic>\u00a0in vivo are elucidated. Cellular protective effects of TMEM16F correlated with its capacity of lipid scrambling and augment PM fluidity. Using cell type\u2010specific TMEM16F\u2010deficient mice, the indication is obtained that\u00a0TMEM16F expressed in liver Kupffer cells (KCs), but not in T cells or B cells, is key for protection against <jats:italic>Listeria<\/jats:italic> in vivo. In the absence of TMEM16F, <jats:italic>Listeria<\/jats:italic> induced PM rupture and fragmentation of KCs in vivo. KC death associated with greater liver damage, inflammatory changes, and dysregulated liver metabolism. Overall, the results uncovered that TMEM16F expressed in Kupffer cells is crucial to protect the host against\u00a0<jats:italic>Listeria<\/jats:italic>\u00a0infection. This influence is associated with the capacity of Kupffer cell\u2010expressed TMEM16F to prevent excessive inflammation and abnormal liver metabolism.<\/jats:p>","DOI":"10.1002\/advs.202402693","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T03:55:44Z","timestamp":1723521344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["TMEM16F Expressed in Kupffer Cells Regulates Liver Inflammation and Metabolism to Protect Against <i>Listeria Monocytogenes<\/i>"],"prefix":"10.1002","volume":"11","author":[{"given":"Jianlong","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Immunology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology (HUST) Wuhan 430030 China"},{"name":"The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology Anhui Medical University  Hefei 230032 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