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Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production

Abstract

Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.

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Funding

This work was supported by China National Natural Science Foundation (grant nos. 82374445, 82303061, 82305233 and 82373179), Shanghai Shuguang Scholar (grant no. 22SG42), Scientific research project of Shanghai Municipal Health Commission (grant no. 20224Z0019), Key Discipline Construction Project of Shanghai Three Year Action Plan for Strengthening the Construction of Public Health System (grant no. GWVI-11.1-24), High-level Chinese Medicine Key Discipline Construction Project (Integrative Chinese and Western Medicine Clinic) of National Administration of TCM (grant no. zyyzdxk-2023065) and Evidence-based dermatology base sponsored by state Administration of Traditional Chinese medicine.

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XL, BZ and MZ did the conception and design. XS, LL and J W performed the development of methodology, acquisition and analysis of data, including animal works and cellular tests, with the assistance of MZ, XL, MW, CW, JC and YZ HY, YS, YX and HL provide support and help on data analysis and interpretation. MZ YX and BZ provided technical or material support. XL, BZ and MZ wrote manuscript with helps from XS, LL and JW.

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Correspondence to Meiling Zhang, Bo Zhu or Xin Li.

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Sun, X., Liu, L., Wang, J. et al. Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production. Cell Mol Immunol 21, 738–751 (2024). https://doi.org/10.1038/s41423-024-01160-y

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