S100A9 Drives the Chronification of Psoriasiform Inflammation by Inducing IL-23/ Type 3 Immunity

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de Melo, Bruno Marcel Silva ; Veras, Flavio Protasio ; Zwicky, Pascale ; Lima, Diogenes ; Ingelfinger, Florian ; Martins, Timna Varela ; Prado, Douglas da Silva ; Scharli, Stefanie ; Publio, Gabriel ; Hiroki, Carlos Hiroji ; Melo, Paulo Henrique ; Saraiva, Andre ; Norbiato, Thaina ; Lima, Leonardo ; Ryffel, Bernhard ; Vogl, Thomas ; Roth, Johannes ; Waisman, Ari ; Nakaya, Helder I. ; Souza, Cacilda da Silva ; Cunha, Fernando Q. ; Cunha, Thiago M. ; Becher, Burkhard ; Alves-Filho, Jose C.

• Document type: Journal article
• Source: JOURNAL OF INVESTIGATIVE DERMATOLOGY; v. 143, n. 9, p. 19-pg., 2023-09-01.

Abstract

Psoriasis is a chronic inflammatory skin disorder driven by the IL-23/type 3 immune response. However, mo-lecular mechanisms sustaining the chronicity of inflammation and psoriatic lesions remain elusive. Combining systematic analyses of several transcriptomic datasets, we delineated gene signatures across human psoriatic skin, identifying S100A9 as one of the most up-regulated genes, which was confirmed in lesioned skin from patients with psoriasis and preclinical psoriasiform skin inflammation models. Genetic ablation or pharma-cologic inhibition of S100A9 alleviated Aldara-induced skin inflammation. By single-cell mapping of human psoriatic skin and bone marrow chimeric mice experiments, we identified keratinocytes as the major source of S100A9. Mechanistically, S100A9 induced IL-23 production by dendritic cells, driving the IL-23/type 3 immunity in psoriasiform skin inflammation. In addition, the cutaneous IL-23/IL-17 axis induced epidermal S100A9 expression in human and experimental psoriasis. Thus, we showed an autoregulatory circuit between keratinocyte-derived S100A9 and IL-23/type 3 immunity during psoriasiform inflammation, identifying a crucial function of S100A9 in the chronification of psoriasis. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/13349-5 - The global impact of S100A9 in the immune response in the psoriasis pathogenesis
• Grantee: Bruno Marcel Silva de Melo
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• 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