Sympathetic Signals Promote Liver Fibrosis by Enabling the Immune Evasion of Hepatic Stellate Cells

In this study, we report for the first time that the density of sympathetic innervationspositively correlates with the severity of liver fibrosis in human patients. Of importance,pharmacologic ablation of local sympathetic inputs can mitigate the mouse model of liver fibrosis,while chemogenetic activation of sympathetic signals exacerbates disease progression. We thendemonstrate that hepatic stellate cells (HSCs), the primary cell type responsible for extracellularfibrous deposition, predominantly express the adrenergic receptor alpha 1b (Adra1b) when activatedby liver damage. The specific deletion of Adra1b in HSCs leads to a reduction in liver fibrosis.Mechanistically, we show that sympathetic signals inhibit the HSC expression of several ligands forthe stimulatory receptors of natural killer (NK) cells and simultaneously up-regulate ligands forinhibitory receptors, thus enabling HSCs to evade the cytolytic action of NK cells.