Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells

Front Immunol. 2024 Apr 22:15:1375340. doi: 10.3389/fimmu.2024.1375340. eCollection 2024.

Abstract

Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.

Keywords: Foxp3; Nrf2; allergic asthma; dimethyl fumarate; nuclear factor E2-related factor 2; regulatory T Cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma* / drug therapy
  • Asthma* / immunology
  • Asthma* / metabolism
  • Cytokines / metabolism
  • Dimethyl Fumarate* / pharmacology
  • Dimethyl Fumarate* / therapeutic use
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2* / metabolism
  • Ovalbumin / immunology
  • Signal Transduction* / drug effects
  • T-Lymphocytes, Regulatory* / drug effects
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism

Substances

  • Cytokines
  • Dimethyl Fumarate
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Ovalbumin

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key R&D Program of China (2022YFC2403000; 2021YFC2400500), the National Natural Science Foundation of China (Grant 32170925;81872454;82003033), Shenzhen Science and Technology Program (KQTD20210811090115019), the Shenzhen Science and Technology Program (JCYJ2022081800807016), the Shenzhen Science and Technology Program (JCYJ2022081800807016), the startup fund of SIAT and CAS, the Natural Science Foundation of Chongqing Grant CSTB2022NSCQ-MSX1069 and CSTC2020JCYJ-MSXMX0252, the Entrepreneurship and Innovation Support Program of Chongqing for overseas Scholars Grant CX2022118.