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PSMB5 Alleviates Ulcerative Colitis by Inhibiting ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis

Liang Han1,2, Yanping Hao2, Xudong Wu2

  • 1Department of Gastroenterology, Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China.

Disease Markers
|September 5, 2022
PubMed

Insights

Proteasome 20S subunit beta 5 (PSMB5) ameliorates ulcerative colitis (UC) by reducing oxidative stress and inhibiting NLRP3-mediated pyroptosis. This study reveals PSMB5

Area of Science:

  • Gastroenterology
  • Immunology
  • Cell Biology

Background:

  • Ulcerative colitis (UC) is a chronic inflammatory disease characterized by intestinal mucosal injury.
  • Pyroptosis, a form of programmed cell death, is induced by inflammatory caspases and plays a role in UC pathogenesis.
  • Proteasome 20S subunit beta 5 (PSMB5) is known to promote cell viability.

Purpose of the Study:

  • To investigate the impact of PSMB5 on intestinal mucosal injury in a dextran sulfate sodium- (DSS-) induced UC mouse model.
  • To elucidate the underlying molecular mechanisms by which PSMB5 affects UC, focusing on pyroptosis and oxidative stress.

Main Methods:

  • Induction of UC in Kunming mice using 3% DSS for 5 days.
  • Assessment of clinical symptoms, body weight, colon length, and histological changes.
  • Measurement of malondialdehyde (MDA) and superoxide dismutase (SOD) levels via ELISA.
  • RT-PCR analysis for IL-1β and IL-18 expression.
  • In vitro studies using HIEC-6 cells treated with lipopolysaccharide (LPS) and PSMB5, with or without inhibitors (Z-VAD-FMK, MCC950) and ROS scavenger (NAC).
  • Evaluation of cell viability, lactate dehydrogenase (LDH) release, and intracellular ROS generation.
  • Western blot analysis for NLRP3 inflammasome components and pyroptosis-related proteins.

Main Results:

  • PSMB5 administration significantly alleviated UC symptoms, including increased body weight and colon length, and decreased disease activity index (DAI), colon macroscopic damage index (CMDI), and histological injury scores.
  • PSMB5 reduced oxidative stress markers (ROS, MDA, SOD) and inhibited histopathological changes in DSS-induced UC mice.
  • In vitro, PSMB5 overexpression in LPS-treated HIEC-6 cells exacerbated inflammatory damage by activating the NLRP3 inflammasome and promoting pyroptosis (increased LDH release, lower cell viability, elevated NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18).
  • N-acetylcysteine (NAC) protected HIEC-6 cells by reversing NLRP3 inflammasome activation and pyroptosis.

Conclusions:

  • PSMB5 ameliorates DSS-induced UC in mice by reducing oxidative stress and inhibiting NLRP3-mediated pyroptosis.
  • PSMB5 may protect intestinal epithelial cells by decreasing ROS generation, thereby suppressing NLRP3 inflammasome activation and pyroptosis.
  • The findings suggest a potential therapeutic role for PSMB5 in managing ulcerative colitis.

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