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| Author(s): |
Luis Eduardo Alves Damasceno
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2023-04-18 |
| Examining board members: |
José Carlos Farias Alves Filho;
Niels Olsen Saraiva Câmara;
Larissa Dias da Cunha;
Renata de Meirelles Santos Pereira
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| Advisor: | José Carlos Farias Alves Filho |
| Abstract | |
Nucleic acids are essential carriers of genetic information in living organisms. It is known that the inflammatory process along with tissue damage results in the release of DNA fragments that may activate immune responses. The STING protein (STimulator of INterferon Genes) is an important intracellular component of the microbial or self- cytoplasmic DNA recognition machinery, classically promoting the expression of type I IFNs. However, STING signaling is mostly associated with innate immune responses, being poorly explored in adaptive immunity cells. TH17 cells comprise a subpopulation of CD4 T lymphocytes implicated in host defense against extracellular bacteria and fungi, but also in promoting inflammation in autoimmune diseases. External and/or intrinsic factors have been described to promote transcriptional, epigenetic and post-translational changes that regulate the functional state of these cells. In fact, TH17 cells have been highlighted for presenting high plasticity according to the context. In this sense, the aim of this study was to evaluate the role of STING on the plasticity and pathogenic potential of TH17 cells. Initially, we observed that STING is expressed and it is functional in TH17 cells, and its activation is able to limit the production of IL-17A, while increasing the expression of IL-10 in vitro. Interestingly, we demonstrated that non-pathogenic TH17 cells express higher levels of STING than those activated under pathogenic conditions. Accordingly, STING activity accompanies reduced expression of the pathogenic marker Il23r and increased expression of Il10 and Cd5l, which are associated with the non-pathogenic state of TH17 cells. Furthermore, we observed that STING-induced effects occur independently of type I IFN signaling. Mechanistically, we noticed that STING-induced IL-10 production partially requires AhR receptor signaling. In parallel, Rorγt and IRF3 are able to interact with each other, and that the active form of IRF3 is found in the nucleus of TH17 cells exclusively after activation of STING. In this scenario, the localization of activated IRF3 in the nucleus coincides with the high expression of Rorγt in this compartment. Indeed, we observed that STING-triggered signaling reduces Rorγt binding to the CNS2 region in the Il17a gene, which is crucial for transcription and expression of IL-17A. In a translational approach, we observed that human TH17 cells activated with STING agonists in vitro recapitulate the effects observed in murine cells. Therefore, our findings reveal an intrinsic role of STING in limiting the pathogenic program of TH17 cells, proposing it as an important pharmacological target for inflammatory diseases mediated by TH17 cells. (AU) | |
| FAPESP's process: | 18/17542-4 - The role of the STING signaling pathway in the regulation of Th17 cell pathogenicity and its implication for autoimmunity |
| Grantee: | Luis Eduardo Alves Damasceno |
| Support Opportunities: | Scholarships in Brazil - Doctorate |