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The global impact of S100A9 in the immune response in the psoriasis pathogenesis

Grant number: 20/13349-5
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): January 30, 2021
Effective date (End): January 29, 2022
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:José Carlos Farias Alves Filho
Grantee:Bruno Marcel Silva de Melo
Supervisor abroad: Burkhard Becher
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Zurich (UZH), Switzerland  
Associated to the scholarship:18/19312-6 - Role of S100A9/TLR4 pathway in the metabolic and functional modulation of keratinocytes and activation of dendritic cells: implications on the Psoriasis pathogenesis, BP.DR

Abstract

Psoriasis is a chronic inflammatory skin disease with hyperproliferation of keratinocytes and a massive accumulation of inflammatory cells in the dermis. The pathogenesis of psoriasis is very complex, involving genetic and environmental factors, however, the exact mechanism of the disease remains poorly understood. We evaluated different public transcriptomics datasets from psoriatic patients to explore new potential mediators that could be important for the physiopathology of psoriasis physiopathology. The most up-regulated cluster of mediators in multiple studies was the antimicrobial peptides, which included genes from the S100 family, such as S100A7, S100A8, S100A9, and S100A12. Interestingly, a recent study suggested a positive correlation between the serum levels of S100A9 and clinical score in patients with psoriasis. However, the exact role of S100A9 in the psoriasis context remains unclear. Therefore, we propose to investigate the role of S100A9 in the pathogenesis of psoriasis, which has been funded by FAPESP. In accordance with our previous data mine, we showed that the expression of S100A9 was abundantly increased in the lesional skin, compared with non-lesional skin from the same psoriatic patient. To assess the role of S100A9 in psoriasis, we employed an animal model of psoriasis-like inflammation induced by imiquimod (IMQ). Both mRNA and protein of S100A9 were increased in the dorsal skin post-IMQ. The S100a9/ mice exhibited significantly less inflammation and decreased epidermal thickness compared to control mice (Figure 2a and b). Additionally, the injection of recombinant mouse S100A9 (rS100A9) intradermally into the ear of C57BL/6 mice induced psoriasis like-pathology, including acanthosis, the infiltration of inflammatory cells, and ear swelling (Figure 2c and d). To validate S100A9 as a therapeutic target in psoriasis, we treated C57BL/6 mice with paquinimod (PAQ- 10 mg.kg-1 v.o.), a scavenger of S100A9, that neutralize its function in vivo. Mechanistically, we showed that S100A9 aggravates the psoriatic inflammation via a positive regulation of the IL-23/IL-17a axis. We are now proposing to explore the global impact of S100A9 in the skin, evaluating which cells or cytokines and chemokines related to the pathogenesis of psoriasis could be modulated by S100A9. Therefore, according to our previous data and the initial goals, we are proposing to explore the global gene profile expression in dendritic cells stimulated with rS100A9, grouping the pathways and genes associated with activation and metabolism (Figure 4). To reach these aims, we have set up a collaborative study with Prof. Dr. Burkhard Becher from the University of Zurich, Zurich, Switzerland, who is an expert in High Dimensional Flow Cytometry with publications in high-impact journals, including Nature Medicine, Immunity, and Cell. To this end, we are applying for the BEPE fellowship program to spend 12 months in his laboratory to develop this project.