Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka 565-0871, Japan; Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka 565-0871, Japan; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka 565-0871, Japan; Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka 565-0871, Japan; Precursory Research for Innovative Medical Care (PRIME), Japan Agency for Medical Research and Development (AMED), Tokyo 100-0004, Japan.
Immunity. 2020 Mar 17;52(3):542-556.e13. doi: 10.1016/j.immuni.2020.02.007.
Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.
纤维化是一种病因不明的不可治愈的疾病。含分离核的非典型单核细胞（SatMs）对于纤维化的发展至关重要。在这里，我们研究了将 SatMs 募集到前纤维化区域的机制。基于纤维化肺中的细胞因子表达进行的筛选表明，趋化因子 Cxcl12 是由凋亡的非造血细胞产生的，对于 SatM 的募集是必需的。在纤维化起始时的肺组织分析中，发现核外切体靶向复合物的组成部分 Rbm7 的表达增加。Rbm7 缺失抑制博来霉素诱导的纤维化，并且在细胞水平上，抑制非造血细胞的凋亡。在机制上，Rbm7 与形成亚核体的非编码（nc）RNA 结合，包括 Neat1 斑点。Rbm7 的失调表达导致 Neat1 斑点的核降解、DNA 修复蛋白 BRCA1 的分散以及细胞凋亡的触发。因此，上皮细胞中的 Rbm7 通过调节 ncRNA 降解，从而产生募集 SatMs 的趋化因子，在纤维化的发展中发挥关键作用。
