Study of bone marrow-liver axis mediated by IL-1R2+ macrophage in alcohol-related liver disease

Abstract

About 80 % of patients with alcoholic steatosis do not progress into alcoholic steatohepatitis, suggesting the existence of unknown protective mechanisms. Recently, some macrophages are known to have anti-inflammatory roles, but their phenotypes and origins are unveiled. I investigated the sub-population of macrophages showing anti-inflammatory roles through scRNA-Seq, the mechanism of monocyte egress from bone marrow (BM), and the regulatory effects of mesenchymal stromal cells (MSCs) on BM monocytes. In alcohol-fed mouse liver, scRNA-Seq revealed high expression of interleukin-1 type II receptor (IL-1R2), decoy receptor of IL-1β in Ly6C$^{low}$ macrophages. Besides, BM leptin receptor (LepR)$^+$ MSCs could metabolize alcohol by alcohol dehydrogenase, and expressed cystine-glutamate anti-porter xCT for glutamate excretion and chemokines (CXCL9 and 10) that recruited CXCR3$^+$ natural killer (NK) cells and stimulated metabotropic glutamate receptor 5 (mGluR5) in NK cells, leading to enhanced production of interferon-γ (IFN-γ). In turn, IFN-γ down-regulated CX3C chemokine receptor 1 (CX3CR1) expression in Ly6C$^{low}$ monocytes bound to chemokine (C-X3-C motif) ligand 1 (CX3CL1)$^+$ MSCs, consequently inducing egress of Ly6C$^{low}$ monocytes into the blood. In conclusion, glutamate LepR$^+$ MSCs granted egress license on IL-1R2$^+$ Ly6C$^{low}$ monocytes through NK/IFN-γ-mediated inhibition of CX3CR1, suggesting a potential therapeutic inter-organ crosstalk between BM and liver in alcohol-related liver disease (ALD).