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

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

doi:10.1016/j.celrep.2022.111897

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

Cell Rep. 2022 Dec 27;41(13):111897. doi: 10.1016/j.celrep.2022.111897.

Authors

Flávio P Veras¹, Gabriel A Publio², Bruno M Melo², Douglas S Prado², Thainá Norbiato², Nerry T Cecilio², Carlos Hiroki², Luis Eduardo A Damasceno², Rebecca Jung³, Juliana E Toller-Kawahisa², Timna V Martins², Stella F Assunção², Diogenes Lima⁴, Marcia G Alves⁵, Gabriel V Vieira⁵, Lucas A Tavares⁵, Ana L R Alves-Rezende⁶, Susanne H Karbach⁷, Helder I Nakaya⁸, Thiago M Cunha², Cacilda S Souza⁶, Fernando Q Cunha², Katiuchia U Sales⁵, Ari Waisman⁹, José C Alves-Filho¹⁰

Affiliations

¹ Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Center of Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany. Electronic address: fprotasio@usp.br.
² Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Center of Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
³ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany.
⁴ Department of Clinical and Toxicological Analyses of the School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
⁵ Department of Cell Biology, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil.
⁶ Division of Dermatology, Internal Medicine Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁷ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany; Center for Cardiology, Cardiology I, Johannes Gutenberg-University Mainz, Mainz, Germany.
⁸ Center of Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Clinical and Toxicological Analyses of the School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil.
⁹ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany.
¹⁰ Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Center of Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: jcafilho@usp.br.

PMID: 36577385
DOI: 10.1016/j.celrep.2022.111897

Abstract

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-κB 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.

Keywords: Act1; CP: Immunology; IL-17A; NF-κB; PKM2; TRAF6; inflammation; keratinocyte; psoriasis; skin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dermatitis*
Inflammation / metabolism
Interleukin-17 / metabolism
Keratinocytes / metabolism
Mice
Psoriasis* / chemically induced
Pyruvate Kinase / metabolism
Skin / metabolism

Substances

Interleukin-17
Pyruvate Kinase