CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease

• Published in: Nature communications Vol. 12; no. 1; pp. 7172 - 11
• Main Authors: Duan, Yi, Chu, Huikuan, Brandl, Katharina, Jiang, Lu, Zeng, Suling, Meshgin, Nairika, Papachristoforou, Eleni, Argemi, Josepmaria, Mendes, Beatriz G., Wang, Yanhan, Su, Hua, Sun, Weizhong, Llorente, Cristina, Hendrikx, Tim, Liu, Xiao, Hosseini, Mojgan, Kisseleva, Tatiana, Brenner, David A., Bataller, Ramon, Ramachandran, Prakash, Karin, Michael, Fu, Wenxian, Schnabl, Bernd
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2504/342; 64/60; 692/308/575; 692/699/1503/1607/1608; Animals; Bacteria; Bacterial Translocation; Complement C3b - immunology; Complement component C3b; Enterococcus faecalis; Enterococcus faecalis - immunology; Enterococcus faecalis - physiology; Ethanol; Ethanol - adverse effects; Female; Gastrointestinal Tract - microbiology; Gram-positive bacteria; Gram-Positive Bacterial Infections - genetics; Gram-Positive Bacterial Infections - immunology; Gram-Positive Bacterial Infections - microbiology; Homeostasis; Humanities and Social Sciences; Humans; Immune clearance; Immunoglobulins; Liver; Liver - drug effects; Liver - immunology; Liver - microbiology; Liver diseases; Liver Diseases, Alcoholic - etiology; Liver Diseases, Alcoholic - genetics; Liver Diseases, Alcoholic - immunology; Liver Diseases, Alcoholic - microbiology; Macrophages; Macrophages - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Phagocytes; Phagocytosis; Receptors; Receptors, Complement - deficiency; Receptors, Complement - genetics; Receptors, Complement - immunology; Receptors, Complement 3b - genetics; Receptors, Complement 3b - immunology; Rodents; Science; Science (multidisciplinary); Toll-like receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27385-3

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg–Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease. CRIg is expressed on liver macrophages and binds Gram-positive bacteria to mediate phagocytosis, but it is not clear how its phagocytic functions contribute to liver homeostasis or disease. Here the authors report that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of alcoholic liver disease.