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

Cellular & Molecular Immunology volume 21, pages 738–751 (2024)Cite this article

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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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References

  1. Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker J. Psoriasis. Lancet. 2021;397:1301–15.

    Article  CAS  PubMed  Google Scholar 

  2. Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. JAMA. 2020;323:1945–60.

    CAS  PubMed  Google Scholar 

  3. Afonina IS, Van Nuffel E, Beyaert R. Immune responses and therapeutic options in psoriasis. Cell Mol Life Sci. 2021;78:2709–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang A, Bai Y. Dendritic cells: the driver of psoriasis. J Dermatol. 2020;47:104–13.

    CAS  PubMed  Google Scholar 

  5. Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci. 2019;20:1475.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, et al. Psoriasis. Nat Rev Dis Primers. 2016;2:16082.

    PubMed  Google Scholar 

  7. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206:1983–94.

  8. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Investig Dermatol. 2009;129:79–88.

    CAS  PubMed  Google Scholar 

  9. Petit RG, Cano A, Ortiz A, Espina M, Prat J, Muñoz M, et al. Psoriasis: from pathogenesis to pharmacological and nano-technological-based therapeutics. Int J Mol Sci. 2021;22:4983.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sato Y, Ogawa E, Okuyama R. Role of innate immune cells in psoriasis. Int J Mol Sci. 2020;21:6604.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Furue M, Furue K, Tsuji G, Nakahara T. Interleukin-17A and keratinocytes in psoriasis. Int J Mol Sci. 2020;21:1275.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng QY, Liang SJ, Xu F, Li GQ, Luo N, Wu S, et al. C5a/C5aR1 pathway is critical for the pathogenesis of psoriasis. Front Immunol. 2019;10:1866.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Conrad C, Gilliet M. Type I IFNs at the interface between cutaneous immunity and epidermal remodeling. J Investig Dermatol. 2012;132:1759–62.

    CAS  PubMed  Google Scholar 

  14. Takagi H, Arimura K, Uto T, Fukaya T, Nakamura T, Choijookhuu N, et al. Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation. Sci Rep. 2016;6:24477.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564–9.

    CAS  PubMed  Google Scholar 

  16. Grine L, Dejager L, Libert C, Vandenbroucke RE. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev. 2015;26:25–33.

    CAS  PubMed  Google Scholar 

  17. Afshar M, Martinez AD, Gallo RL, Hata TR. Induction and exacerbation of psoriasis with Interferon-alpha therapy for hepatitis C: a review and analysis of 36 cases. J Eur Acad Dermatol Venereol. 2013;27:771–8.

    CAS  PubMed  Google Scholar 

  18. Ketikoglou I, Karatapanis S, Elefsiniotis I, Kafiri G, Moulakakis A. Extensive psoriasis induced by pegylated interferon alpha-2b treatment for chronic hepatitis B. Eur J Dermatol. 2005;15:107–9.

    PubMed  Google Scholar 

  19. van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182:5836–45.

    PubMed  Google Scholar 

  20. Karthaus N, van Spriel AB, Looman MWG, Chen S, Spilgies LM, Lieben L, et al. Vitamin D controls murine and human plasmacytoid dendritic cell function. J Investig Dermatol. 2014;134:1255–64.

    CAS  PubMed  Google Scholar 

  21. Suzuki T, Tatsuno K, Ito T, Sakabe JI, Funakoshi A, Tokura Y. Distinctive downmodulation of plasmacytoid dendritic cell functions by vitamin D3 analogue calcipotriol. J Dermatol Sci. 2016;84:71–79.

    CAS  PubMed  Google Scholar 

  22. Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther. 2021;6:291.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339:786–91.

    CAS  PubMed  Google Scholar 

  24. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Li Q, Liu C, Yue R, El-Ashram S, Wang J, He X, et al. cGAS/STING/TBK1/IRF3 signaling pathway activates BMDCs maturation following mycobacterium bovis infection. Int J Mol Sci. 2019;20:895.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lima-Junior DS, Krishnamurthy SR, Bouladoux N, Collins N, Han SJ, Chen EY, et al. Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota. Cell. 2021;184:3794–811.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fischer K, Tschismarov R, Pilz A, Straubinger S, Carotta S, McDowell A, et al. Cutibacterium acnes infection induces Type I interferon synthesis through the cGAS-STING pathway. Front Immunol. 2020;11:571334.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Li T, Yum S, Li M, Chen X, Zuo X, Chen ZJ. TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance. J Exp Med. 2022;219:e20211539.

    CAS  PubMed  Google Scholar 

  29. Yu Y, Xue X, Tang W, Su L, Zhang L, Zhang Y. Cytosolic DNA‒mediated STING-dependent inflammation contributes to the progression of psoriasis. J Investig Dermatol. 2022;142:898–906.

    CAS  PubMed  Google Scholar 

  30. Di Domizio J, Belkhodja C, Chenuet P, Fries A, Murray T, Mondéjar PM, et al. The commensal skin microbiota triggers type I IFN-dependent innate repair responses in injured skin. Nat Immunol. 2020;21:1034–45.

    PubMed  Google Scholar 

  31. Skopelja-Gardner S, An J, Elkon KB. Role of the cGAS-STING pathway in systemic and organ-specific diseases. Nat Rev Nephrol. 2022;18:558–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hägg D, Sundström A, Eriksson M, Schmitt-Egenolf M. Decision for biological treatment in real life is more strongly associated with the Psoriasis Area and Severity Index (PASI) than with the Dermatology Life Quality Index (DLQI). J Eur Acad Dermatol Venereol. 2015;29:452–6.

    PubMed  Google Scholar 

  33. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF. NF-κB: an essential transcription factor in psoriasis. J Dermatol Sci. 2013;69:89–94.

    CAS  PubMed  Google Scholar 

  34. Swindell WR, Xing X, Stuart PE, Chen CS, Aphale A, Nair RP, et al. Heterogeneity of inflammatory and cytokine networks in chronic plaque psoriasis. PLoS ONE. 2012;7:e34594.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kwon HK, Patra MC, Shin HJ, Gui X, Achek A, Panneerselvam S, et al. A cell-penetrating peptide blocks Toll-like receptor-mediated downstream signaling and ameliorates autoimmune and inflammatory diseases in mice. Exp Mol Med. 2019;51:1–19.

    PubMed  PubMed Central  Google Scholar 

  36. Cai Y, Xue F, Quan C, Qu M, Liu N, Zhang Y, et al. A critical role of the IL-1β-IL-1R signaling pathway in skin inflammation and psoriasis pathogenesis. J Investig Dermatol. 2019;139:146–56.

    CAS  PubMed  Google Scholar 

  37. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin-12 is increased in psoriatic skin. J Investig Dermatol. 1998;111:1053–7.

    CAS  PubMed  Google Scholar 

  38. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–46.

    CAS  PubMed  Google Scholar 

  39. Vacaflores A, Chapman NM, Harty JT, Richer MJ, Houtman JC. Exposure of human CD4 T cells to IL-12 results in enhanced TCR-induced cytokine production, altered tcr signaling, and increased oxidative metabolism. PLoS ONE. 2016;11:e0157175.

    PubMed  PubMed Central  Google Scholar 

  40. Prinz JC, Gross B, Vollmer S, Trommler P, Strobel I, Meurer M, et al. T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol. 1994;24:593–8.

    CAS  PubMed  Google Scholar 

  41. Baker BS, Swain AF, Fry L, Valdimarsson H. Epidermal T lymphocytes and HLA-DR expression in psoriasis. Br J Dermatol. 1984;110:555–64.

    CAS  PubMed  Google Scholar 

  42. Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Investig Dermatol. 1994;102:145–9.

    CAS  PubMed  Google Scholar 

  43. Reich K, Warren RB, Lebwohl M, Gooderham M, Strober B, Langley RG, et al. Bimekizumab versus Secukinumab in Plaque Psoriasis. N Engl J Med. 2021;385:142–52.

    CAS  PubMed  Google Scholar 

  44. Xiaohong L, Zhenting Z, Yunjie Y, Wei C, Xiangjin X, Kun X, et al. Activation of the STING-IRF3 pathway involved in psoriasis with diabetes mellitus. J Cell Mol Med. 2022;26:2139–51.

    PubMed  PubMed Central  Google Scholar 

  45. Andres-Ejarque R, Ale HB, Grys K, Tosi I, Solanky S, Ainali C, et al. Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis. Nat Commun. 2021;12:4741.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang L, Wei X, Wang Z, Liu P, Hou Y, Xu Y, et al. NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking. Cell Rep. 2023;42:112185.

    CAS  PubMed  Google Scholar 

  47. Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021;21:548–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lai CY, Su YW, Lin KI, Hsu LC, Chuang TH. Natural modulators of endosomal Toll-like receptor-mediated psoriatic skin inflammation. J Immunol Res. 2017;2017:7807313.

    PubMed  PubMed Central  Google Scholar 

  49. Suzuki T, Sakabe J, Kamiya K, Funakoshi A, Tokura Y. The Vitamin D3 analogue calcipotriol suppresses CpG-activated TLR9-MyD88 signalling in murine plasmacytoid dendritic cells. Clin Exp Dermatol. 2018;43:445–8.

    CAS  PubMed  Google Scholar 

  50. Pan Y, You Y, Sun L, Sui Q, Liu L, Yuan H, et al. The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation. Br J Pharmacol. 2021;178:4907–22.

    CAS  PubMed  Google Scholar 

  51. Kim JH, Choi YJ, Lee BH, Song MY, Ban CY, Kim J, et al. Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1-high T cells. J Allergy Clin Immunol. 2016;137:1466–76.

    CAS  PubMed  Google Scholar 

  52. Wang W, Li J, Wu K, Azhati B, Rexiati M. Culture and identification of mouse bone marrow-derived dendritic cells and their capability to induce T lymphocyte proliferation. Med Sci Monit Int Med J Exp Clin Res. 2016;22:244–50.

    CAS  Google Scholar 

  53. Zhu B, Zhang M, Byrum SD, Tackett AJ, Davie JK. TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells. Int J Cancer. 2014;135:785–97.

    CAS  PubMed  PubMed Central  Google Scholar 

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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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Author notes

  1. These authors contributed equally: Xiaoying Sun, Liu Liu, Jiao Wang.

Authors and Affiliations

  1. Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China

    Xiaoying Sun, Liu Liu, Jiao Wang, Chunxiao Wang, Jiale Chen, Yaqiong Zhou, Hongjin Li & Xin Li

  2. Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China

    Xiaoying Sun, Liu Liu, Jiao Wang, Chunxiao Wang, Jiale Chen, Yaqiong Zhou, Hongjin Li & Xin Li

  3. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China

    Xiaorong Luo, Meng Wang & Bo Zhu

  4. Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA

    Hang Yin

  5. Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Yuanbin Song

  6. Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510006, China

    Yuanyan Xiong

  7. Medical Research Institute, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, 510080, China

    Meiling Zhang

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Contributions

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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