Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis

  • Immunity. 2020 Mar 17;52(3):542-556.e13. doi: 10.1016/j.immuni.2020.02.007.
Kiyoharu Fukushima  1 ,  Takashi Satoh  2 ,  Fuminori Sugihara  3 ,  Yuki Sato  4 ,  Toru Okamoto  5 ,  Yuichi Mitsui  1 ,  Sachiyo Yoshio  6 ,  Songling Li  7 ,  Satoshi Nojima  8 ,  Daisuke Motooka  9 ,  Shota Nakamura  9 ,  Hiroshi Kida  10 ,  Daron M Standley  7 ,  Eiichi Morii  8 ,  Tatsuya Kanto  6 ,  Motoko Yanagita  11 ,  Yoshiharu Matsuura  5 ,  Takashi Nagasawa  12 ,  Atsushi Kumanogoh  10 ,  Shizuo Akira  13
Affiliations
  • 1. 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.
  • 2. 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. Electronic address: [email protected].
  • 3. Laboratory of Biofunctional Imaging, WPI-IFReC, Osaka University, Osaka 565-0871, Japan.
  • 4. Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Medical Innovation Center TMK Project, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
  • 5. Department of Molecular Virology, RIMD, Osaka University, Osaka 565-0871, Japan.
  • 6. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan.
  • 7. Department of Genome Informatics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 8. Department of Pathology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 9. Genome Information Research Center, RIMD, Osaka University, Osaka 565-0871, Japan.
  • 10. Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 11. Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
  • 12. Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, WPI-IFReC, Osaka University, Osaka 565-0871, Japan.
  • 13. 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. Electronic address: [email protected].
PMID: 32187520 DOI: 10.1016/j.immuni.2020.02.007
Abstract

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.

Keywords
RNA decay; fibrosis; innate immunity; macrophage; ncRNA.