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

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.

Immune Response of an Oral Enterococcus faecalis Phage Cocktail in a Mouse Model of Ethanol-Induced Liver Disease

“…We observed that oral phage treatment can upregulate F4/80 , a marker of resident Kupffer cells in the liver [ 25 ]. Kupffer cells play a crucial role in the phagocytosis of translocated bacteria; thus, an increased number of the first will increase the clearance of the latter [ 18 ]. An in vitro study with Staphylococcus aureus and Pseudomonas aeruginosa phages demonstrated the production of both inflammatory and anti-inflammatory cytokines from peripheral blood mononuclear cells (the prevailing effect being anti-inflammatory) [ 4 ].…”

Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute‐on‐chronic alcohol‐induced liver injury

“…In addition, innate immunity and the complement system have been implicated in many facets of ALD (Santiesteban‐Lores et al, 2021). While some complement factors are protective and some harmful in the pathogenesis of ALD, it seems that the induction of this pathway in E8G3 may function to protect against bacterial translocation similar to acute phase response (Cohen et al, 2010; Duan et al, 2021; Roychowdhury et al, 2009). Another pathway that changed in our analysis was oxidative phosphorylation between E8G1 and E8G3.…”

Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus

“…The lack of IL-17 receptor might promote intestinal dysbiosis and LPS translocation into visceral adipose tissue by inhibiting the migration of neutrophils in the intestinal mucosa, leading to glucose intolerance and insulin resistance in HFD-fed mice ( Pérez et al, 2019 ). Complement receptor of the immunoglobulin superfamily (CRIg) is expressed on human macrophages and plays an important role in immune responses ( Duan et al, 2021 ). Luo et al observed an accumulation of EVs containing gut microbial DNAs and a decrease in the number of liver CRIg + macrophages in obesity ( Luo et al, 2021 ).…”