Abstract
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.
Highlights
Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis
Recent single-cell RNA-seq studies of healthy and diseased human liver have defined heterogeneity in hepatic macrophages[29,30], distinguishing transcriptionally distinct populations of tissue-resident Kupffer cells (KC), tissue monocytes (TMo), and scar-associated macrophages (SAMac) which expand in patients with chronic liver disease[30]
Fewer KC were present in patients with alcohol-related cirrhosis (Fig. 1b and Supplementary Fig. 1a), whilst assessment of marker expression in whole liver tissue demonstrated that patients with alcohol-related liver disease had reduced expression of other Kupffer cell marker genes (TIMD4, CD5L and MARCO) and increased expression of scar-associated macrophage marker genes (TREM2 and CD9) (Fig. 1d, e and Supplementary Fig. 1b–d)
Summary
Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. 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. We recently found that the presence of cytolysin-positive (cytolytic) Enterococcus faecalis (E. faecalis) in the intestine correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. CRIg can directly, and independent of complement, bind to lipoteichoic acid—one of the cell wall components of Gram-positive bacteria—to support hepatic capture of circulating bacteria[25]. We investigated whether absence of CRIg or administration of a soluble CRIg-Ig protein affects progression of ethanol-induced liver disease via alteration in hepatic clearance of pathobionts
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
