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  3. TMEM16F Expressed in Kupffer Cells Regulates Liver Inflammation and Metabolism to Protect Against Listeria Monocytogenes

TMEM16F Expressed in Kupffer Cells Regulates Liver Inflammation and Metabolism to Protect Against Listeria Monocytogenes

  • Adv Sci (Weinh). 2024 Aug 13:e2402693. doi: 10.1002/advs.202402693.
Jianlong Tang 1 2,  Hua Song 1,  Shimin Li 3,  Sin Man Lam 4 5,  Jieming Ping 1 2,  Mengyun Yang 1 2,  Na Li 6,  Teding Chang 7,  Ze Yu 8,  Weixiang Liu 1 2,  Yan Lu 9,  Min Zhu 10,  Zhaohui Tang 7,  Zheng Liu 8,  Yusong R Guo 6 11,  Guanghou Shui 4 5,  André Veillette 12 13 14,  Zhutian Zeng 3 15,  Ning Wu 1 2 11
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, 430030, China.
  • 2 The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, 230032, China.
  • 3 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 4 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
  • 5 University of Chinese Academy of Sciences, Beijing, 100101, China.
  • 6 Department of biochemistry and molecular biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 7 Department of Traumatic Surgery, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 8 Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, China.
  • 9 Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 10 Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 11 Cell Architecture Research Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 12 Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, H2W1R7, Canada.
  • 13 Department of Medicine, University of Montréal, Montréal, Québec, H3T 1J4, Canada.
  • 14 Department of Medicine, McGill University, Montréal, Québec, H3G 1Y6, Canada.
  • 15 Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, China.
PMID: 39136057 DOI: 10.1002/advs.202402693
Abstract

Infection by bacteria leads to tissue damage and inflammation, which need to be tightly controlled by host mechanisms to avoid deleterious consequences. It is previously reported that TMEM16F, a calcium-activated lipid scramblase expressed in various immune cell types including T cells and neutrophils, is critical for the control of Infection by bacterium Listeria monocytogenes (Lm) 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 Lm toxin listeriolysin O (LLO). However, whether the protective effect of TMEM16F on Lm 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 Lm in vivo are elucidated. Cellular protective effects of TMEM16F correlated with its capacity of lipid scrambling and augment PM fluidity. Using cell type-specific TMEM16F-deficient mice, the indication is obtained that TMEM16F expressed in liver Kupffer cells (KCs), but not in T cells or B cells, is key for protection against Listeria in vivo. In the absence of TMEM16F, Listeria 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 Listeria Infection. This influence is associated with the capacity of Kupffer cell-expressed TMEM16F to prevent excessive inflammation and abnormal liver metabolism.

Keywords

TMEM16F; inflammation; kupffer cell; lipid scrambling; listeria monocytogenes; macrophage; plasma membrane integrity.

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