Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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.
Cell Rep. 2024 Jul 23;43(7):114400. doi: 10.1016/j.celrep.2024.114400. Epub 2024 Jun 26.
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 ADAR1 tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
ADAR1 介导的 RNA 编辑通过防止其感应来建立对内源性双链 RNA (dsRNA) 的免疫耐受，主要通过 MDA5。虽然删除 Ifih1（编码 MDA5）可以挽救 ADAR1 缺陷小鼠的胚胎致死，但它们仍然会在出生后早期死亡，并且去除其他 MDA5 信号蛋白不会产生相同的挽救效果。在这里，我们表明，在肝特异性 Adar 敲除 (KO) 小鼠模型中敲除 MDA5 不能挽救 ADAR1 缺失引起的肝异常。Ifih1;Adar 双重 KO (dKO) 肝细胞积累内源性 dsRNA，导致异常过渡到高度炎症状态，并将巨噬细胞募集到 dKO 肝脏中。在机制上，颗粒蛋白前体 (PGRN) 似乎介导 ADAR1 缺乏诱导的肝病理，促进干扰素信号，并将表皮生长因子受体 (EGFR) 巨噬细胞吸引到 dKO 肝中，加重肝炎症。值得注意的是，ADAR1 肿瘤中明显抑制了 PGRN-EGFR 串扰通讯和随之而来的免疫反应，表明前瘤或瘤细胞可以利用 ADAR1 依赖性免疫耐受来促进免疫逃逸。
