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Role of S100A9/TLR4 pathway in the metabolic and functional modulation of keratinocytes and activation of dendritic cells: implications on the Psoriasis pathogenesis

Grant number: 18/19312-6
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2019
Effective date (End): July 31, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:José Carlos Farias Alves Filho
Grantee:Bruno Marcel Silva de Melo
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Psoriasis (Ps) is a skin inflammatory disease characterized by infiltration of immune system cells with activation and hyperproliferation of keratinocytes. These cells can reprogram energy metabolism, increasing the expression of pro-glycolytic molecules, an essential event for the development of experimental Ps. In conditions of activation or stress, keratinocytes produce various inflammatory mediators, including the S100A9 protein. This molecule has been associated with some inflammatory diseases, including Ps. During my Master degree study, we demonstrated that the expression of S100A9 is increased in the lesioned skin of patients with Ps, which positively correlates with the genes expression related with keratinocytes proliferation. The increase of S100A9 expression in the skin was also observed in different experimental Psoriasis models. We have shown that keratinocytes are the main source of this alarmin, being responsible for the increase of the thickness of the epidermis, which is a classic histological parameter of Psoriasis. Our data demonstrated that S100A9 induces the production of IL-23 in dendritic cells, which positively regulates the IL-23/IL-17 axis, suggesting a new mechanism by which this molecule would be involved in the development of Ps. However, previous studies suggest an autocrine role of this molecule in the activation of keratinocytes. Therefore, knowing that S100A9 can act via TLR4 receptor and this receptor is also increased in activated keratinocytes and in patients' skin. Thus, our aim is to investigate the S100A9/TLR4 pathway in metabolic reprogramming and function of keratinocytes and activation of dendritic cells. Although we have advanced in the characterization and functional role of S100A9 in the development of Psoriasis in model animal, suggesting a new mechanism for this molecule, our data open new possibility to study the role of this alarmin in different cells, such as keratinocytes and dendritic cell cells, both essential for the pathogenesis of Ps. (AU)