Local sympathetic signal enables the immune evasion of hepatic stellate cells.

The liver has local sympathetic inputs, but their involvement in fibrosis is incompletely understood. Here, we report that the density of sympathetic axons positively correlates with the severity of liver fibrosis in human patients. Importantly, sympathetic ablation mitigates the mouse model of CCl4-induced liver fibrosis, whereas chemogenetic activation of local sympathetic signals exacerbates disease. Activated mouse or human hepatic stellate cells (HSCs), the primary cell type responsible for extracellular fibrous deposition, predominantly express the α1B-adrenergic receptor (ADRA1B) for the sympathetic neurotransmitter norepinephrine, and HSC-specific Adra1b deletion in mice effectively reduces liver fibrosis. We then show that ADRA1B-mediated sympathetic signaling in HSCs decreases the expression of specific ligands for activating receptors of natural killer (NK) cells but upregulates the ligands for inhibitory NK receptors, thereby enabling immune evasion of HSCs from NK cell cytotoxicity. These results elucidate a previously unrecognized neuroimmune mechanism underlying the sympathetic regulation of liver pathology.