1. Academic Validation
  2. USP13-mediated IRAK4 deubiquitination disrupts the pathological symptoms of lipopolysaccharides-induced sepsis

USP13-mediated IRAK4 deubiquitination disrupts the pathological symptoms of lipopolysaccharides-induced sepsis

  • Microbes Infect. 2021 Nov-Dec;23(9-10):104867. doi: 10.1016/j.micinf.2021.104867.
Zhigao Wang 1 Long Jiang 1 Daquan Zhang 1 Dong Chen 1 Lu Wang 1 Dong Xiao 2
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, People's Hospital of Xinjiang Uygur Autonomous Region, No.91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China.
  • 2 Department of Critical Care Medicine, People's Hospital of Xinjiang Uygur Autonomous Region, No.91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China. Electronic address: [email protected].
Abstract

Ubiquitin-specific peptidase 13 (USP13) has been reported to participate in tumorigenesis, cell cycle arrest, endoplasmic reticulum-associated degradation, and immune responses. Here, we explored the function of USP13 in pro-inflammatory cytokine production of macrophages and its role in mouse sepsis model. Primary bone-marrow-derived macrophages (BMDMs) isolated from wild type (WT) and USP13MKO mice were treated by lipopolysaccharides (LPS), IL-4, toll-like receptors (TLRs) agonists, and IRAK4 Inhibitor to profile the inflammatory responses with different genotypes. Mouse sepsis model (WT and USP13MKO) created by intraperitoneal injection with LPS plus d-galactosamine was used to assess septic shock-induced survival and lung inflammation. Flow cytometry, qRT-PCT, Western blot, and ELISA were performed to detect pro-inflammatory production and macrophage polarization. USP13 was a key regulator of IRAK4 deubiquitination in BMDMs and its myeloid specific deficiency contributed to LPS-induced pro-inflammatory response and septic symptoms. IRAK4 Inhibitor co-administration improved in LPS-induced inflammatory responses in both BMDMs and septic mice. USP13 negatively regulates LPS-induced sepsis shock by targeting IRAK4. In summary, targeting USP13-IRAK4 axis might be a potential therapeutic strategy for the treatment of inflammation in sepsis shock.

Keywords

Deubiquitination; IRAK4; Macrophage; Sepsis shock; USP13.

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