USP10 regulates macrophage inflammation responses via stabilizing NEMO in LPS-induced sepsis

Inflamm Res. 2023 Aug;72(8):1621-1632. doi: 10.1007/s00011-023-01768-2. Epub 2023 Jul 12.


Background: Sepsis is a systemic inflammatory response syndrome characterized by persistent inflammation and immunosuppression, leading to septic shock and multiple organ dysfunctions. Ubiquitin-specific peptidase 10 (USP10), a deubiquitinase enzyme, plays a vital role in cancer and arterial restenosis, but its involvement in sepsis is unknown.

Objective: In this study, we investigated the significance of USP10 in lipopolysaccharide (LPS)-stimulated macrophages and its biological roles in LPS-induced sepsis.

Methods: Lipopolysaccharides (LPS) were used to establish sepsis models in vivo and in vitro. We use western blot to identify USP10 expression in macrophages. Spautin-1 and USP10-siRNA were utilized for USP10 inhibition. ELISA assays were used to assess for TNF-α and IL-6 in vitro and in vivo. Nuclear and cytoplasmic protein extraction and Confocal microscopy were applied to verify the translocation of NF-κB. Mechanically, co-immunoprecipitation and rescue experiments were used to validate the regulation of USP10 and NEMO.

Results: In macrophages, we found that LPS induced USP10 upregulation. The inhibition or knockdown of USP10 reduced the pro-inflammatory cytokines TNF-α and IL-6 and suppressed LPS-induced NF-κB activation by regulating the translocation of NF-κB. Furthermore, we found that NEMO, the regulatory subunit NF-κB essential modulator, was essential for the regulation of LPS-induced inflammation by USP10 in macrophages. NEMO protein evidently interacted with USP10, whereby USP10 inhibition accelerated the degradation of NEMO. Suppressing USP10 significantly attenuated inflammatory responses and improved the survival rate in LPS-induced sepsis mice.

Conclusions: Overall, USP10 was shown to regulate inflammatory responses by stabilizing the NEMO protein, which may be a potential therapeutic target for sepsis-induced lung injury.

Keywords: Deubiquitinase; Inflammation; NEMO; Sepsis; USP10.

MeSH terms

  • Animals
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Interleukin-6 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Mice
  • NF-kappa B* / metabolism
  • Sepsis* / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • NEMO protein, mouse
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • USP10 protein, mouse