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Dural Tregs driven by astrocytic IL-33 mitigate depression through the EGFR signals in mPFC neurons

Cell Death & Differentiation volume 32, pages 926–943 (2025)Cite this article

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Abstract

The dura sinus-resident immune cells can influence the process of central neural system (CNS) diseases by communicating with central nerve cells. In clinical, Tregs are also frequently impaired in depression. However, the significance of this relationship remains unknown. In the present study, we found a significant increase in dural Treg populations in mouse models of depression, whereas depleting them by neutralizing antibodies injection could exacerbate depressive phenotypes. Through RNA sequencing, we identified that the antidepressant effects of dural Tregs are at least in part through the production of amphiregulin, increasing the expression of its receptor EGFR in medial prefrontal cortex (mPFC) pyramidal neurons. Furthermore, dural Tregs expressed high levels of ST2, and their expansion in depressed mice depended on astrocyte-derived IL33 secretion. Our study shows that dural Treg signaling can be enhanced by treatment with fluoxetine, highlighting that dural Tregs can be utilized as a potential target cell in major depressive disorder (MDD).

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Fig. 1: CSDS stimulation induced significant infiltration of Tregs in the dura mater of mice.
Fig. 2: Single-cell RNA sequencing characterizes CSDS-induced transcriptome changes in dural immune cells.
Fig. 3: Depressive stress enhances dura mater infiltration of Tregs by activating ST2 signaling.
Fig. 4: IL33/ST2 signaling may be involved in the increase of dural Tregs after CSDS stressing.
Fig. 5: IL33 secreted by brain astrocytes induced by depressive stress may be involved in the increase of dural Tregs.
Fig. 6: Depletion of dural Tregs exacerbates CSDS-induced depressive behaviors.
Fig. 7: AREG secreted by dural Tregs may regulate depressive behaviors by influencing the activity of mPFC neurons.
Fig. 8: Dural Tregs regulate depressive behaviors by activating EGFR signaling in mPFC pyramidal neurons.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The datasets used in the current study are available on the Sequence Read Archive (SRA) repository (No. PRJNA1177115; https://submit.ncbi.nlm.nih.gov/subs/sra/). Additional data are available from authors upon request.

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Funding

National Key R&D Program of China (No. 2021ZD0202903). National Natural Science Foundation of China (Nos. 82373851, 81922066, 82173797, 81991523).

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Author notes

  1. These authors contributed equally: Hang Yao, Yang Liu.

Authors and Affiliations

  1. Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China

    Hang Yao, Yueping Wang, Siyuan Jiang, Xin Sun, Jianhua Ding, Gang Hu & Ming Lu

  2. The Second People’s Hospital of Changzhou, Changzhou Medical Center, Nanjing Medical University, Nanjing, China

    Hang Yao & Ming Lu

  3. Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Yang Liu, You Xue & Gang Hu

  4. Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, China

    Minjun Ji & Zhipeng Xu

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Contributions

Experimental operation: Hang Yao, Yuepin Wang, You Xue, Siyuan Jiang, Xin Sun. Data acquisition: Hang Yao, Yang Liu. Figure drafting: Hang Yao, Yang Liu. Manuscript writing: Hang Yao, Yang Liu. Single-cell sequencing analysis guidance: Zhipeng Xu, Minjun Ji. Technical supporting: Jianhua Ding. Study designing and manuscript revising: Ming Lu, Gang Hu.

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Correspondence to Gang Hu or Ming Lu.

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Yao, H., Liu, Y., Wang, Y. et al. Dural Tregs driven by astrocytic IL-33 mitigate depression through the EGFR signals in mPFC neurons. Cell Death Differ 32, 926–943 (2025). https://doi.org/10.1038/s41418-024-01421-3

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