GARP on hepatic stellate cells is essential for the development of liver fibrosis

• Published in: Journal of hepatology 2023-11, Vol.79 (5), p.1214-1225
• Main Authors: Zhang, Xiaolong, Sharma, Pankaj, Maschmeyer, Patrick, Hu, Yu, Lou, Mumeng, Kim, Jessica, Fujii, Hodaka, Unutmaz, Derya, Schwabe, Robert F., Winau, Florian
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; endothelin-1 (ET-1); Endothelin-1 - metabolism; GARP; hepatic stellate cells (HSCs); Hepatic Stellate Cells - metabolism; Humans; Interleukin-4 - metabolism; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; liver fibrosis; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; natural killer T (NKT) cells; TGF-β; Transforming Growth Factor beta - metabolism
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2023.05.043

Glycoprotein A repetitions predominant (GARP) is a membrane protein that functions as a latent TGF-β docking molecule. While the immune regulatory properties of GARP on blood cells have been studied, the function of GARP on tissue stromal cells remains unclear. Here, we investigate the role of GARP expressed on hepatic stellate cells (HSCs) in the development of liver fibrosis. The function of GARP on HSCs was explored in toxin-induced and metabolic liver fibrosis models, using conditional GARP-deficient mice or a newly generated inducible system for HSC-specific gene ablation. Primary mouse and human HSCs were isolated to evaluate the contribution of GARP to the activation of latent TGF-β. Moreover, cell contraction of HSCs in the context of TGF-β activation was tested in a GARP-dependent fashion. Mice lacking GARP in HSCs were protected from developing liver fibrosis. Therapeutically deleting GARP on HSCs alleviated the fibrotic process in established disease. Furthermore, natural killer T cells exacerbated hepatic fibrosis by inducing GARP expression on HSCs through IL-4 production. Mechanistically, GARP facilitated fibrogenesis by activating TGF-β and enhancing endothelin-1-mediated HSC contraction. Functional GARP was expressed on human HSCs and significantly upregulated in the livers of patients with fibrosis. Lastly, deletion of GARP on HSCs did not augment inflammation or liver damage. GARP expressed on HSCs drives the development of liver fibrosis via cell contraction-mediated activation of latent TGF-β. Considering that systemic blockade of TGF-β has major side effects, we highlight a therapeutic niche provided by GARP and surface-mediated TGF-β activation. Thus, our findings suggest an important role of GARP on HSCs as a promising target for the treatment of liver fibrosis. Liver fibrosis represents a substantial and increasing public health burden globally, for which specific treatments are not available. Glycoprotein A repetitions predominant (GARP) is a membrane protein that functions as a latent TGF-β docking molecule. Here, we show that GARP expressed on hepatic stellate cells drives the development of liver fibrosis. Our findings suggest GARP as a novel target for the treatment of fibrotic disease. [Display omitted] •GARP on HSCs contributes to the development of liver fibrosis through TGF-β activation.•Natural killer T cells induce GARP expression on HSCs by producing IL-4.•GARP-mediated cell contraction forms a vicious cycle driving fibr