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Published on: December 19, 2019
Prolyl hydroxylase inhibition protects against murine MC903-induced skin inflammation by downregulating TSLP
Anupriya Gupta1, Mi Hye Song1, Dong Hyuk Youn2
1Department of Pathology, Hallym University College of Medicine, Chuncheon, Republic of Korea.
Abstract:
Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.
Insights
Dimethyloxalylglycine (DMOG) reduces skin inflammation by downregulating thymic stromal lymphopoietin (TSLP) and reactive oxygen species (ROS) via the hypoxia-inducible factor (HIF) pathway.
Area of Science:
- Dermatology
- Immunology
- Molecular Biology
Background:
- Previous studies indicated an anti-inflammatory role for mTORC1 in type 2 skin inflammation.
- Dimethyloxalylglycine (DMOG) inhibited thymic stromal lymphopoietin (TSLP) upregulation, but its precise mechanism in skin inflammation was unclear.
Purpose of the Study:
- To investigate the protective effects of DMOG against MC903 (calcipotriol)-induced type 2 skin inflammation.
- To elucidate the molecular mechanisms underlying DMOG's anti-inflammatory action, focusing on TSLP, IL-33, reactive oxygen species (ROS), and the hypoxia-inducible factor (HIF) pathway.
Main Methods:
- MC903-induced type 2 skin inflammation model in mice.
- Histopathological analysis (H&E staining), flow cytometry, and quantitative real-time PCR (RT-qPCR).
- Assessment of TSLP, IL-33, ROS levels, and the impact of N-acetylcysteine (NAC) and HIF knockdown.
Main Results:
- DMOG treatment attenuated MC903-induced skin inflammation independently of T cells.
- DMOG downregulated TSLP and IL-33 expression; recombinant TSLP and IL-33 reversed DMOG's protective effect.
- DMOG inhibited MC903-induced ROS production, an effect mimicked by NAC.
- DMOG's effects on ROS and TSLP were diminished by HIF knockdown.
Conclusions:
- DMOG exerts a protective effect against MC903-induced type 2 skin inflammation.
- The anti-inflammatory mechanism involves the downregulation of TSLP and ROS through the HIF pathway.
- DMOG represents a potential therapeutic agent for type 2 skin inflammatory conditions.
