Celastrol Activates HSF1 to Enhance Regulatory T Cells Function and Ameliorate Intestinal Inflammation

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition resulting from dysregulation of the intestinal immune system. CD4⁺FoxP3⁺ regulatory T cells (Tregs) play a crucial role in regulating this immune response. The heat shock response (HSR) regulates the inflammatory cascade, preventing misfolding of proteins and regulating immune responses. We have previously shown that Heat Shock Factor 1 (HSF1), the master regulator of the HSR, regulates Tregs in inflammation. Based on this finding, we hypothesized that targeting HSF1 with celastrol, a pentacyclic triterpenoid that activates HSF1, would activate Treg cells and ameliorate intestinal inflammation. To test this, we investigated the impact of celastrol on Tregs both in vitro and in vivo, evaluating its efficacy in HSF1^fl/fl-CD4^cre mice, and in two murine models of IBD: the adoptive transfer colitis, and TNF^ΔARE+/- ileitis. Our results demonstrate that celastrol activates HSF1 in Tregs, enhances Treg suppressive function, increases Treg populations in vivo, and ameliorates intestinal inflammation.