S100A9 drives the chronification of psoriasiform inflammation by inducing IL-23-dependent type 3 immunity

Author(s)

Bruno Marcel Silva de Melo

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-01-25

Examining board members

José Carlos Farias Alves Filho; Marcelo Torres Bozza; João Santana da Silva; Mauro Martins Teixeira

• Advisor: José Carlos Farias Alves Filho

Abstract

Psoriasis (Ps) is the most prevalent chronic inflammatory skin disease, affecting approximately 2-3% of the world\'s population. The etiology of psoriasis involves both genetic susceptibility and environmental factors. The disease is characterized by increased thickness of the epidermis due to marked activation and proliferation of keratinocytes. Dysregulated crosstalk between factors released by keratinocytes and immune cells in the skin is thought to be the initial trigger of the IL-23/IL-17 circuit that mediates cutaneous inflammation in psoriasis. However, the exact mechanisms responsible for the development and chronicity of the disease remain poorly understood. Thus, our study initially aimed to identify new targets with potential impact on the pathogenesis of psoriasis. For this, we reanalyzed different public databases of patients with psoriasis and through in silico analyzes we were able to identify the transcriptional profile of the skin of these patients. We identified the dominantly enhanced antimicrobial peptide pathway, which is enriched by several genes, with emphasis on the genes of the S100A family, including S100A7, S100A8, S100A9 and S100A12. Among all identified targets of the S100A family, S100A9 has been one of the most correlated with disease activity in patients with psoriasis, however, its exact mechanism in the disease remains poorly understood. In this sense, our study aimed to investigate the function and mechanisms by which S100A9 modulates the cutaneous inflammatory response in psoriasis. From skin and blood samples from patients with psoriasis, we noticed an increase in the expression of S100A9 in the skin lesion and in the plasma of these patients, compared to healthy control skin and blood. Increased S100A9 gene and protein expression was also observed in murine skin in an IMQ-induced psoriasiform model. Functionally, we demonstrate that genetic absence or pharmacological blockade of S100A9 attenuates the cutaneous inflammatory response in an IMQ-induced psoriasiform model. Complementing these data, the intradermal injection of S100A9 induces an active inflammatory process in the skin, with similarities, at least in part, to those observed in psoriasis. Through scRNAseq analyses, we identified interfollicular keratinocytes as the main source of S100A9 in the injured skin of patients with psoriasis. Supporting these findings, through bone marrow transfer assays, we demonstrate that non-hematopoietic cell-derived S100A9 mediates the inflammatory response in the IMQ-induced psoriasiform model. Through high-parameter spectral flow cytometry we demonstrated that S100A9 exacerbates the cutaneous inflammatory response by enhancing type 3 immunity. Furthermore, S100A9 induces IL-23 production, activation and metabolic reprogramming of dendritic cells via TLR4 in vitro. Additionally, we identified that S100A9-mediated psoriasiform effects depend on IL-23 in different experimental models of psoriasis. Taken together, we demonstrate that S100A9 exacerbates psoriasiform inflammation through induction of IL-23-dependent type 3 immunity. Furthermore, we demonstrate that the cutaneous inflammatory axis IL-23/IL-17 induces S100A9 expression in keratinocytes in psoriasis. Taken together, our data reveal an autoregulatory circuit between S100A9 and IL-23/type 3 immunity, essential for the chronification of psoriasiform inflammation. (AU)

• FAPESP's process: 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
• Grantee: Bruno Marcel Silva de Melo
• Support Opportunities: Scholarships in Brazil - Doctorate