| First Author | Shim YR | Year | 2026 |
| Journal | Clin Mol Hepatol | PubMed ID | 42315151 |
| Mgi Jnum | J:392167 | Mgi Id | MGI:8408098 |
| Doi | 10.3350/cmh.2026.0425 | Citation | Shim YR, et al. (2026) Glutamate excreted by LepR(+) BM-MSCs mitigates alcohol-associated liver disease by promoting IL-1R2(+) monocyte migration. Clin Mol Hepatol |
| abstractText | BACKGROUND/AIMS: Bone marrow mesenchymal stromal cells (BM-MSCs) exert diverse functions, including supporting alcohol detoxification and providing a niche for monocyte development. However, their role in regulating monocytes during alcohol-related liver disease (ALD) remains unclear. This study investigates how BM-MSCs orchestrate the egress of anti-inflammatory monocytes from BM to the liver in ALD. METHODS: Wild-type, leptin receptor (LepR)(+) BM-MSC-specific Slc7a11 knockout, and natural killer (NK) cell-specific Grm5 knockout mice were fed an ethanol diet for 8 weeks. Tissue analyses were performed using single-cell RNA sequencing (scRNA-seq), immunostaining, and flow cytometry. Blood and liver samples from ALD patients were examined. RESULTS: scRNA-seq revealed a distinct population of BM-derived Ly6Clow hepatic macrophages expressing interleukin-1 receptor 2 (IL-1R2), an IL-1beta decoy receptor, in ethanol-fed mice. In the BM, alcohol exposure upregulated the gene expression of alcohol-metabolizing enzymes (Adh1, Aldh2), xCT (Slc7a11), and chemokines (Cxcl9, Cxcl10) in LepR+ BM-MSCs, promoting NK cell recruitment and interferon-gamma (IFN-gamma) production via metabotropic glutamate receptor 5 (mGluR5) activation. Subsequently, IFN-gamma enhanced IL-1R2 expression and suppressed CX3CR1 in neighboring Ly6Clow BM monocytes, facilitating their hepatic migration. LepR+ BM-MSC-specific xCT and NK cell-specific mGluR5 knockout mice exhibited exacerbated liver injury and elevated blood IL-1beta levels, while recombinant IL-1R2 administration improved ameliorated ALD in wild-type mice. Consistently, increased IL-1R2 levels were observed in plasma, CD14+CD16+ blood monocytes, and liver tissues of ALD patients. CONCLUSIONS: We identified a BM-liver axis in which glutamate released by BM-MSCs activates mGluR5 in BM NK cells, driving IL-1R2+ monocyte migration to the liver and attenuating ALD progression. |
