Highlights
- •CX3CR1 is predominantly expressed by M1 liver macrophages.
- •CX3CR1 deficiency exacerbates the progression of NASH by regulating macrophages.
- •Transplantation of Cx3cr1−/− bone marrow causes hepatic inflammation and fibrosis.
- •CCL2 deletion in Cx3cr1−/− mice alleviates NASH progression.
- •Overexpression of CX3CL1 in vivo protects against hepatic fibrosis in NASH.
Abstract
Background and objectives
Chemokine (C-X3-C motif) ligand 1 (CX3CL1) and its receptor CX3CR1 regulate the migration
and activation of immune cells and are involved in the pathogenesis of nonalcoholic
steatohepatitis (NASH), but the mechanism remains elusive. Here, the roles of CX3CL1/CX3CR1
in the macrophage migration and polarization in the livers of NASH mice were investigated.
Methods and results
The expression of Cx3cl1 and Cx3cr1 was markedly upregulated in the livers of lipotoxicity-induced NASH mice. CX3CR1
was predominantly expressed by F4/80+ macrophages and to a lesser degree by hepatic stellate cells or endothelial cells
in the livers of NASH mice. Flow cytometry analysis revealed that, compared with chow-fed
mice, NASH mice exhibited a significant increase in CX3CR1+ expression by liver macrophages (LMs), particularly M1 LMs. CX3CR1 deficiency caused
a significant increase in inflammatory monocyte/macrophage infiltration and a shift
toward M1 dominant macrophages in the liver, thereby exacerbating the progression
of NASH. Moreover, transplantation of Cx3cr1−/− bone marrow was sufficient to cause glucose intolerance, inflammation, and fibrosis
in the liver. In addition, deletion of CCL2 in Cx3cr1−/− mice alleviated NASH progression by decreasing macrophage infiltration and inducing
a shift toward M2 dominant LMs. Importantly, overexpression of CX3CL1 in vivo protected
against hepatic fibrosis in NASH.
Conclusion
Pharmacological therapy targeting liver CX3CL1/CX3CR1 signaling might be a candidate
for the treatment of NASH.
Abbreviations:
Acc (acetyl-coenzyme A carboxylase), Acox (acyl-coenzyme A oxidase 1), Apo (apolipoprotein), α-SMA (alpha-smooth muscle actin), ALT (alanine aminotransferase), AST (aspartate aminotransferase), Ccl (chemokine (CC motif) ligand,), Ccr (C-C chemokine receptor type), Cd36 (cluster of differentiation), Chrebp (carbohydrate-responsive element-binding protein), Col1a1 (collagen, type I, alpha 1), Cpt1a (carnitine palmitoyltransferase 1a), Fasn (fatty acid synthase), HSC (hepatic stellate cell), Il (interleukin), KC (Kupffer cell), Lcad (long-chain acyl-CoA dehydrogenase), Lcat (lecithin-cholesterol acyltransferase), Lpl (lipoprotein lipase), Lxr (liver x receptor), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), NEFA (non-esterified fatty acids), Mttp (microsomal triglyceride transfer protein), Pai-1 (plasminogen activator inhibitor-1), Pgc (peroxisome proliferative activated receptor-gamma coactivator), Ppar (peroxisome proliferator activated receptor), Scd (stearoyl-coenzyme A desaturase), Srebp (sterol regulatory element-binding protein), TBARS (thiobarbituric acid reactive substances), TC (total cholesterol), Tgf (transforming growth factor), TG (triglyceride), Tnf (tumor necrosis factor)Keywords
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Article info
Publication history
Published online: July 28, 2022
Accepted:
July 26,
2022
Received:
April 21,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
