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无法治愈的疾病。分离出的含核非典型单核细胞（SatMs）对于纤维化的发展至关重要。在这里，我们研究了将SatM募集到纤维化前区域的机制。基于纤维化肺中细胞因子表达的筛选显示，由凋亡的非造血细胞产生的趋化因子Cxcl12对SatM募集至关重要。纤维化发作时对肺组织的分析显示Rbm7的表达增加，Rbm7是核外泌体靶向复合物的组成部分。Rbm7删除抑制博来霉素诱导的纤维化，并在细胞水平上抑制非造血细胞的凋亡。从机制上讲，Rbm7与形成亚核小体（包括Neat1）的非编码（nc）RNA结合斑点。Rbm7的表达失调导致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衰变并从而产生募集SatMs的趋化因子，在纤维化的发展中起关键作用。