Advanced Science (Oct 2023)

The Deubiquitinase OTUD1 Suppresses Secretory Neutrophil Polarization And Ameliorates Immunopathology of Periodontitis

  • Jia Song,
  • Yuning Zhang,
  • Yunyang Bai,
  • Xiaowen Sun,
  • Yanhui Lu,
  • Yusi Guo,
  • Ying He,
  • Min Gao,
  • Xiaopei Chi,
  • Boon Chin Heng,
  • Xin Zhang,
  • Wenjing Li,
  • Mingming Xu,
  • Yan Wei,
  • Fuping You,
  • Xuehui Zhang,
  • Dan Lu,
  • Xuliang Deng

DOI
https://doi.org/10.1002/advs.202303207
Journal volume & issue
Vol. 10, no. 30
pp. n/a – n/a

Abstract

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Abstract Tissue‐infiltrating neutrophils (TINs) secrete various signaling molecules to establish paracrine communication within the inflammatory milieu. It is imperative to identify molecular mediators that control this secretory phenotype of TINs. The present study uncovers a secretory neutrophil subset that exhibits increased pro‐inflammatory cytokine production and enhanced migratory capacity which is highly related with periodontal pathogenesis. Further analysis identifies the OTU domain‐containing protein 1 (OTUD1) plays a regulatory role in this secretory neutrophil polarization. In human and mouse periodontitis, the waning of inflammation is correlated with OTUD1 upregulation, whereas severe periodontitis is induced when neutrophil‐intrinsic OTUD1 is depleted. Mechanistically, OTUD1 interacts with SEC23B, a component of the coat protein II complex (COPII). By removing the K63‐linked polyubiquitin chains on SEC23B Lysine 81, the deubiquitinase OTUD1 negatively regulates the COPII secretory machinery and limits protein ER‐to‐Golgi trafficking, thus restricting the surface expression of integrin‐regulated proteins, CD9 and CD47. Accordingly, blockade of protein transport by Brefeldin A (BFA) curbs recruitment of Otud1‐deficient TINs and attenuates inflammation‐induced alveolar bone destruction. The results thus identify OTUD1 signaling as a negative feedback loop that limits the polarization of neutrophils with secretory phenotype and highlight the potential application of BFA in the treatment of periodontal inflammation.

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