ADAR1 promotes systemic sclerosis via modulating classic macrophage activation.
ADAR1 promotes systemic sclerosis via modulating classic macrophage activation.
复制标题
DOI：
10.3389/fimmu.2022.1051254
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
系统性硬化症(SSC)是一种以皮肤和其他内脏器官炎症和纤维化为特征的多系统自身免疫性疾病。然而，推动SSc发展的炎症反应的潜在机制在很大程度上仍不清楚。用ADAR1杂合基因敲除(AD1+/-)小鼠和髓系特异性ADAR1基因敲除小鼠检测ADAR1在SSC中的功能。组织病理学分析和免疫印迹证实ADAR1在博莱霉素诱导的皮肤和肺纤维化增加中起作用。在本研究中，我们发现作用于RNA的腺苷脱氨酶(ADAR1)是一种在RNA中将腺苷转化为肌苷的脱氨酶(即RNA编辑)，在博莱霉素诱导的SSC早期，巨噬细胞中大量表达ADAR1。重要的是，ADAR1对于SSc的形成是必不可少的，也是经典巨噬细胞激活所不可缺少的，因为巨噬细胞中ADAR1缺乏显著改善皮肤和肺硬化症，并抑制巨噬细胞中炎症介质诱导型一氧化氮合酶(INOS)和IL-1β的表达。从机制上讲，ADAR1的缺失通过减少NF-κB信号来阻断巨噬细胞的激活。我们的研究表明，ADAR1促进了SSC发病过程中巨噬细胞的活化。因此，靶向ADAR1可能成为治疗硬化症的一种潜在的新的治疗策略。
As a multisystem autoimmune disorder disease, systemic sclerosis (SSc) is characterized by inflammation and fibrosis in the skin and other internal organs. However, mechanisms underlying the inflammatory response that drives the development of SSc remain largely unknown. ADAR1 heterozygous knockout (AD1+/-) mice and myeloid-specific ADAR1 knockout mice were used to determine the function of ADAR1 in SSc. Histopathological analyses and western blot confirmed the role of ADAR1 in bleomycin-induced increased skin and lung fibrosis. In this study, we discover that adenosine deaminase acting on RNA (ADAR1), a deaminase converting adenosine to inosine (i.e., RNA editing) in RNA, is abundantly expressed in macrophages in the early stage of bleomycin-induced SSc. Importantly, ADAR1 is essential for SSc formation and indispensable for classical macrophage activation because ADAR1 deficiency in macrophages significantly ameliorates skin and lung sclerosis and inhibits the expression of inflammation mediator inducible NO synthase (iNOS) and IL-1β in macrophages. Mechanistically, deletion of ADAR1 blocks macrophage activation through diminishing NF-κB signaling. Our studies reveal that ADAR1 promotes macrophage activation in the onset of SSc. Thus, targeting ADAR1 could be a potential novel therapeutic strategy for treating sclerosis formation.
登录
查看更多内容
影响因子：
5.4
作者：
Ciechomska, Marzena;Wojtas, Bartosz;Maslinski, Wlodzimierz
通讯作者：
Maslinski, Wlodzimierz
ADAR1结合的基因组分析及其参与多个RNA处理途径。
影响因子：
16.6
作者：
Bahn, Jae Hoon;Ahn, Jaegyoon;Lin, Xianzhi;Zhang, Qing;Lee, Jae-Hyung;Civelek, Mete;Xiao, Xinshu
通讯作者：
Xiao, Xinshu
影响因子：
64.8
作者：
Lawrence, T;Bebien, M;Karin, M
通讯作者：
Karin, M
影响因子：
7.3
作者：
Maria, Alexandre T. J.;Rozier, Pauline;Noel, Daniele
通讯作者：
Noel, Daniele
影响因子：
64.8
作者：
Ishizuka, Jeffrey J.;Manguso, Robert T.;Haining, W. Nicholas
通讯作者：
Haining, W. Nicholas