NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis

• DOI: 10.1126/sciimmunol.add1599
• Publication Date: 2023-09-29T17:58:43Z
• Authors: Sonja Marinović; Maja Lenartić; Karlo Mladenić; Marko Šestan; Inga Kavazović; Ante Benić; Mia Krapić; Lukas Rindlisbacher; Maja Cokarić Brdo...; Colin Sparano; Gioana Litscher; Tamara Turk Wensveen; Ivana Mikolašević; Dora Fučkar Čupić; Lidija Bilić-Zulle; Aleksander Steinle; Ari Waisman; Adrian Hayday; Sonia Tugues; Burkhard Becher; Bojan Polić; Felix M. Wensveen
• Keywords: NKG2D; Steatohepatitis; Proinflammatory cytokine; Hepatic stellate cell; Steatosis

Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology MAFLD development nonalcoholic steatohepatitis (NASH), which can potentially lead fibrosis and hepatocellular carcinoma, but triggers MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation hepatocytes induces expression ligands specific activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ activated through NKG2D secrete IL-17A. IL-17A licenses produce chemokines recruit proinflammatory cells into liver, causes NASH fibrosis. NKG2D-deficient mice did develop dietary models had decreased incidence hepatic tumors. The frequency + blood patients with correlated directly pathology. Our findings identify molecular mechanism stressed trigger context MAFLD.