1. Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.
- Author
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Gan WL, Ren X, Ng VHE, Ng L, Song Y, Tano V, Han J, An O, Xie J, Ng BYL, Tay DJT, Tang SJ, Shen H, Khare S, Chong KHC, Young DY, Wu B, DasGupta R, and Chen L
- Subjects
- Animals, Mice, Signal Transduction, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Humans, Intercellular Signaling Peptides and Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Mice, Inbred C57BL, RNA, Double-Stranded metabolism, RNA Editing, Adenosine Deaminase metabolism, Adenosine Deaminase genetics, ErbB Receptors metabolism, Macrophages metabolism, Macrophages immunology, Progranulins metabolism, Progranulins genetics, Liver metabolism, Liver immunology, Liver pathology, Hepatocytes metabolism, Interferon-Induced Helicase, IFIH1 metabolism, Interferon-Induced Helicase, IFIH1 genetics, Mice, Knockout
- Abstract
ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)
+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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