Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver
Wei Liang Gan,
Xi Ren,
Vanessa Hui En Ng,
Larry Ng,
Yangyang Song,
Vincent Tano,
Jian Han,
Omer An,
Jinghe Xie,
Bryan Y.L. Ng,
Daryl Jin Tai Tay,
Sze Jing Tang,
Haoqing Shen,
Shruti Khare,
Kelvin Han Chung Chong,
Dan Yock Young,
Bin Wu,
Ramanuj DasGupta,
Leilei Chen
Affiliations
Wei Liang Gan
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Xi Ren
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Vanessa Hui En Ng
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Larry Ng
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Yangyang Song
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Vincent Tano
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Jian Han
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Omer An
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Jinghe Xie
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, P.R. China
Bryan Y.L. Ng
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Daryl Jin Tai Tay
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Sze Jing Tang
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Haoqing Shen
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Shruti Khare
Genome Institute of Singapore, Agency for Science Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore, Singapore
Kelvin Han Chung Chong
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore
Dan Yock Young
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
Bin Wu
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore
Ramanuj DasGupta
Genome Institute of Singapore, Agency for Science Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore, Singapore
Leilei Chen
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Corresponding author
Summary: 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.
