研究揭示纖維化發生的機制
作者：
小柯機器人發布時間：2020/3/18 21:11:10
日本大阪大學Shizuo Akira和Takashi Satoh研究團隊合作發現，非造血細胞中核外泌體靶向複合物組分Rbm7的表達失調導致纖維化的發展。這一研究成果發表在2020年3月17日出版的《免疫學》上。
纖維化是一種病因不明的無法治癒疾病，SatMs對於纖維化的發展至關重要。
在本研究中，研究人員揭示了將含有分離核的非典型性單核細胞（SatMs）招募到纖維化前區的機制。基於肺纖維化中細胞因子表達的篩選顯示，由凋亡非造血細胞產生的趨化因子Cxcl12對於SatM招募至關重要。
纖維化發生時對肺組織的分析顯示Rbm7的表達增加，Rbm7是核外泌體靶向複合物的組分。敲出Rbm7抑制了博來黴素誘導的纖維化，並在細胞水平上抑制非造血細胞的凋亡。
從機制上看，Rbm7與形成亞核小體（包括Neat1斑點）的非編碼（nc）RNA結合。 Rbm7表達失調導致Neat1斑點的核降解、DNA修復蛋白BRCA1的分解和細胞凋亡的發生。
因此，上皮細胞中的Rbm7通過調控ncRNA降解來產生招募SatMs的趨化因子，從而在纖維化的發展中起關鍵作用。
附：英文原文
Title: Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis
Author: Kiyoharu Fukushima, Takashi Satoh, Fuminori Sugihara, Yuki Sato, Toru Okamoto, Yuichi Mitsui, Sachiyo Yoshio, Songling Li, Satoshi Nojima, Daisuke Motooka, Shota Nakamura, Hiroshi Kida, Daron M. Standley, Eiichi Morii, Tatsuya Kanto, Motoko Yanagita, Yoshiharu Matsuura, Takashi Nagasawa, Atsushi Kumanogoh, Shizuo Akira
Issue&Volume: 2020/03/17
Abstract: Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containingatypical monocytes (SatMs) are critical for the development of fibrosis. Here we examinedthe mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokineexpression in the fibrotic lung revealed that the chemokine Cxcl12, which is producedby apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analysesof lung tissues at fibrosis onset showed increased expression of Rbm7, a componentof the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressedapoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAsthat form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation ofNeat1 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 fibrosisby regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.
DOI: 10.1016/j.immuni.2020.02.007
Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30078-9