Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1β production

Mol Immunol. 2018 Dec:104:11-19. doi: 10.1016/j.molimm.2018.09.004. Epub 2018 Nov 3.

Abstract

Background: NLRP3 inflammasome mediates IL-1β maturation, therefore plays a vital role in the development of IBD. Curcumin is known for possessing strong anti-inflammatory property.

Objective: The present study was to investigate the protective effects of curcumin on dextran sulfate sodium (DSS)-induced colitis through inhibiting NLRP3 inflammasome activation and IL-1β production.

Methods: LPS-primed macrophages were treated with curcumin prior to DSS triggering NLRP3 inflammasome activation, IL-1β secretion and ASC oligomerization were observed. The mechanisms of curcumin in the inhibition of DSS-induced inflammasome activation were explored. Curcumin or caspase-1/NLRP3 inhibitor was administrated respectively in DSS-induced colitis mouse model. The changes of body weight, disease activity index, colon length were measured. Additionally, mature IL-1β and other inflammatory cytokines, MPO activity and histopathological damage were analyzed for the evaluation of colitis severity.

Results: NLRP3 inflammasome activation was dramatically inhibited by curcumin in DSS-stimulated macrophages, as evidenced by decreased IL-1β secretion, less caspase-1 activation and ASC specks. Mechanistically, curcumin prevented DSS-induced K+ efflux, intracellular ROS formation and cathepsin B release, three major cellular events mediating NLRP3 inflammasome activation. In DSS-induced colitis, curcumin administration significantly ameliorated colitis symptoms by reducing weight loss, DAI and colon length shortening. Meanwhile, curcumin significantly decreased the expression of multiple inflammatory cytokines (including mature IL-1β, IL-6, MCP-1), MPO activity, caspase-1 activity as well as histopathological damage. Furthermore, blockage of NLRP3 inflammasome activation in vivo with specific NLRP3 inhibitor abrogated the further inhibitory effect of curcumin on DSS-induced colitis.

Conclusion: Curcumin could strongly suppress DSS-induced NLRP3 inflammsome activation and alleviate DSS-induced colitis in mice, thus it may be a promising candidate drug in clinical application for IBD therapy.

Keywords: Curcumin; Dextran sulfate sodium; IL-1β; Inflammatory bowel diseases; NLRP3 inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 1 / immunology
  • Colitis* / chemically induced
  • Colitis* / immunology
  • Colitis* / pathology
  • Colitis* / prevention & control
  • Curcumin / pharmacology*
  • Dextran Sulfate / toxicity*
  • Female
  • Inflammasomes / immunology*
  • Interleukin-1beta / immunology*
  • Lipopolysaccharides / toxicity
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / pathology
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*

Substances

  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Dextran Sulfate
  • Caspase 1
  • Curcumin