Type 1 Innate Lymphoid Cells Protect Mice from Acute Liver Injury via Interferon-γ Secretion for Upregulating Bcl-xL Expression in Hepatocytes

Tsukasa Nabekura; Luke Riggan; Andrew D Hildreth; Timothy E O'Sullivan; Akira Shibuya

doi:10.1016/j.immuni.2019.11.004

Type 1 Innate Lymphoid Cells Protect Mice from Acute Liver Injury via Interferon-γ Secretion for Upregulating Bcl-xL Expression in Hepatocytes

Immunity. 2020 Jan 14;52(1):96-108.e9. doi: 10.1016/j.immuni.2019.11.004. Epub 2019 Dec 3.

Authors

Tsukasa Nabekura¹, Luke Riggan², Andrew D Hildreth², Timothy E O'Sullivan³, Akira Shibuya⁴

Affiliations

¹ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Immunology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; R&D Center for Innovative Drug Discovery, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
² Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Immunology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; R&D Center for Innovative Drug Discovery, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: ashibuya@md.tsukuba.ac.jp.

Abstract

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl₄) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-γ (IFN-γ) and protected mice from CCl₄-induced acute liver injury. IFN-γ released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-γ production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-γ production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.

Keywords: ATP; Bcl-xL; CCl(4); DNAM-1; IFN-γ; IL-12; IL-7; ILC1; acute liver injury; hepatocyte.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Antigens, Differentiation, T-Lymphocyte / genetics
Antigens, Differentiation, T-Lymphocyte / metabolism
Carbon Tetrachloride / toxicity
Cells, Cultured
Chemical and Drug Induced Liver Injury / prevention & control*
Female
Hepatocytes / metabolism*
Interferon-gamma / immunology*
Interleukin-12 Subunit p35 / immunology
Killer Cells, Natural / immunology
Liver / cytology*
Liver / immunology
Liver / injuries
Lymphocyte Activation / immunology
Lymphocytes / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
bcl-X Protein / metabolism*

Substances

Antigens, Differentiation, T-Lymphocyte
Bcl2l1 protein, mouse
CD226 antigen
IFNG protein, mouse
Il12a protein, mouse
Interleukin-12 Subunit p35
bcl-X Protein
Interferon-gamma
Adenosine Triphosphate
Carbon Tetrachloride

Abstract

Publication types

MeSH terms

Substances

Grant support