Pyruvate kinase M2 mediates IL-17 signaling in keratinocytes driving psoriatic skin inflammation

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Veras, Flavio P. ; Publio, Gabriel A. ; Melo, Bruno M. ; Prado, Douglas S. ; Norbiato, Thaina ; Cecilio, Nerry T. ; Hiroki, Carlos ; Damasceno, Luis Eduardo A. ; Jung, Rebecca ; Toller-Kawahisa, Juliana E. ; Martins, Timna, V ; Assuncao, Stella F. ; Lima, Diogenes ; Alves, Marcia G. ; Vieira, Gabriel V. ; Tavares, Lucas A. ; Alves-Rezende, Ana L. R. ; Karbach, Susanne H. ; Nakaya, Helder I. ; Cunha, Thiago M. ; Souza, Cacilda S. ; Cunha, Fernando Q. ; Sales, Katiuchia U. ; Waisman, Ari ; Alves-Filho, Jose C.

• Tipo de documento: Artigo Científico
• Fonte: CELL REPORTS; v. 41, n. 13, p. 23-pg., 2022-12-27.

Resumo

Psoriasis is an inflammatory skin disease characterized by keratinocyte proliferation and inflammatory cell infiltration induced by IL-17. However, the molecular mechanism through which IL-17 signaling in keratinocytes triggers skin inflammation remains not fully understood. Pyruvate kinase M2 (PKM2), a glycolytic enzyme, has been shown to have non-metabolic functions. Here, we report that PKM2 mediates IL-17A signaling in keratinocytes triggering skin psoriatic inflammation. We find high expression of PKM2 in the epidermis of psoriatic patients and mice undergoing psoriasis models. Specific depletion of PKM2 in keratinocytes attenuates the development of experimental psoriasis by reducing the production of pro -inflammatory mediators. Mechanistically, PKM2 forms a complex with Act1 and TRAF6 regulating NF-KB transcriptional signaling downstream of the IL-17 receptor. As IL-17 also induces PKM2 expression in keratinocytes, our findings reveal a sustained signaling circuit critical for the psoriasis-driving effects of IL-17A, suggesting that PKM2 is a potential therapeutic target for psoriasis. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/10867-0 - Desenvolvimento de queratinócitos da linhagem HaCaT nocautes para a enzima PKM2
• Beneficiário: Gabriel Azevedo Públio
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica