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

Marinović, Sonja; Lenartić, Maja; Mladenić, Karlo; Šestan, Marko; Kavazović, Inga; Benić, Ante; Krapić, Mia; Rindlisbacher, Lukas; Cokarić Brdovčak, Maja; Sparano, Colin; Litscher, Gloana; Turk Wensveen, Tamara; Mikolašević, Ivana; Fučkar Čupić, Dora; Bilić-Zulle, Lidija; Steinle, Alexander; Waisman, Ari; Hayday, Adrian; Tugues, Sonia; Becher, Burkhard; Polić, Bojan; Wensveen, Felix Martinus (2023) NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis. Science Immunology, 8 (87). ISSN 2470-9468

| Request a personal copy from author

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.

Item Type:	Article
Uncontrolled Keywords:	NKG2D; NKGD2D ligands; MAFLD; MASLD; NAFLD; IL-17A; NASH; metabolic cellular stress; inflammation fibrosis
Subjects:	BIOMEDICINE AND HEALTHCARE BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Immunology
Divisions:	Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Imunosni mehanizmi u razvoju upale i metaboličkog sindroma u debljini-INFLAMETAB Bojan Polić IP-2016-06-9306 HRZZ Uloga stanica urođene imunosti u razvoju nealkoholnog steatohepatitisa (NASH) i fibroze jetre- Bojan Polić uniri-biomed-18-89 NadSve Mehanizmi imunološkog prepoznavanja u jetri i njihova uloga u razvoju nealkoholnog steatohepatitisa-MITRAS Bojan Polić IPCH-2020-10-8440 HRZZ Mehanizmi imunološkog nadzora u razvoju metabolički uzrokovane bolesti masne jetre- Maja Lenartić 100.21.0006 VLASTITA-SREDSTVA Mehanizmi imunološkog prepoznavanja u jetri i njihova uloga u razvoju nealkoholnog steatohepatitisa-MITRAS Bojan Polić IPCH-2020-10-8440 HRZZ Preuređivanje memorije: Manipuliranje T-staničnom memorijom u svrhu unapređenja učinkovitosti cjepiva-T-MEMORY Felix Martinus Wensveen IP-2016-06-8027 HRZZ Manipuliranje imunološkom memorijom: razvoj novih strategija u svrhu stvaranja boljeg memorijskog CD8 T-staničnog odgovora protiv COVID-19 nakon cijepljenja-CORONAWAI Felix Martinus Wensveen; Klaas van Gisbergen; Paul Klarenbeek; Jan Koster IP-CORONA-2020-04-2045 HRZZ Utjecaj šećerne bolesti tipa 2 i njezinog liječenja na funkciju limfocita-DIABOLYC Tamara Turk Wensveen; Marija Troskot Dijan IP-2020-02-7928 HRZZ Jačanje kapaciteta CERVIRVAC-a za istraživanja u virusnoj imunologiji i vakcinologiji- Stipan Jonjić KK.01.1.1.01.0006 EK
Depositing User:	Sonja Marinović
Date Deposited:	12 Dec 2025 07:32
URI:	http://fulir.irb.hr/id/eprint/10400
DOI:	10.1126/sciimmunol.add1599

Actions (login required)

View Item