NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis
Sonja Marinović, Maja Lenartić, Karlo Mladenić, Marko Šestan, Inga Kavazović, Ante Benić, Mia Krapić, Lukas Rindlisbacher, Maja Cokarić Brdovčak, Colin Sparano, Gioana Litscher, Tamara Turk Wensveen, Ivana Mikolašević, Dora Fučkar Čupić, Lidija Bilić-Zulle, Aleksander Steinle, Ari Waisman, Adrian Hayday, Sònia Tugues, Burkhard Becher, Bojan Polić, Felix M. Wensveen
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A + γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.