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

• Published in: Microbes and infection Vol. 23; no. 9-10; p. 104867
• Main Authors: Wang, Zhigao, Jiang, Long, Zhang, Daquan, Chen, Dong, Wang, Lu, Xiao, Dong
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.11.2021
• Subjects: Animals; Deubiquitination; Disease Models, Animal; Endoplasmic Reticulum-Associated Degradation; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; IRAK4; Lipopolysaccharides; Macrophage; Mice; Mice, Inbred C57BL; Sepsis; Sepsis shock; Signal Transduction; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; USP13; USP13; Sepsis shock; IRAK4; Deubiquitination; Macrophage
• ISSN: 1286-4579; 1769-714X
• DOI: 10.1016/j.micinf.2021.104867

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.