Microtubule-dependent mechanism of anti-inflammatory effect of SOCS1 in endothelial dysfunction and lung injury

Pratap Karki, Boyoung Cha, Chen Ou Zhang, Yue Li, Yunbo Ke, Kamoltip Promnares, Kozo Kaibuchi, Akihiko Yoshimura, Konstantin G. Birukov, Anna A. Birukova

Research output: Contribution to journalArticlepeer-review

Abstract

Suppressors of cytokine signaling (SOCS) provide negative regulation of inflammatory reaction. The role and precise cellular mechanisms of SOCS1 in control of endothelial dysfunction and barrier compromise associated with acute lung injury remain unexplored. Our results show that siRNA-mediated SOCS1 knockdown augmented lipopolysaccharide (LPS)-induced pulmonary endothelial cell (EC) permeability and enhanced inflammatory response. Consistent with in vitro data, EC-specific SOCS1 knockout mice developed more severe lung vascular leak and accumulation of inflammatory cells in bronchoalveolar lavage fluid. SOCS1 overexpression exhibited protective effects against LPS-induced endothelial permeability and inflammation, which were dependent on microtubule (MT) integrity. Biochemical and image analysis of unstimulated EC showed SOCS1 association with the MT, while challenge with LPS or MT depolymerizing agent colchicine impaired this association. SOCS1 directly interacted with N2 domains of MT-associated proteins CLIP-170 and CLASP2. Furthermore, N-terminal region of SOCS1 was indispensable for these interactions and SOCS1-ΔN mutant lacking N-terminal 59 amino acids failed to rescue LPS-induced endothelial dysfunction. Depletion of endogenous CLIP-170 or CLASP2 abolished SOCS1 interaction with Toll-like receptor-4 and Janus kinase-2 leading to impairment of SOCS1 inhibitory effects on LPS-induced inflammation. Altogether, these findings suggest that endothelial barrier protective and anti-inflammatory effects of SOCS1 are critically dependent on its targeting to the MT.

Original languageEnglish
Article numbere21388
JournalFASEB Journal
Volume35
Issue number4
DOIs
Publication statusPublished - 04-2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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