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

Flávio P Veras1, Gabriel A Publio2, Bruno M Melo2

  • 1Department 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.

Cell Reports
|December 28, 2022
PubMed

Insights

Pyruvate kinase M2 (PKM2) drives psoriasis inflammation by mediating IL-17 signaling in skin cells. Depleting PKM2 reduces psoriatic symptoms, highlighting PKM2 as a potential therapeutic target for psoriasis.

Area of Science:

  • Dermatology
  • Immunology
  • Molecular Biology

Background:

  • Psoriasis is an inflammatory skin condition driven by IL-17.
  • The precise molecular pathways linking IL-17 signaling to keratinocyte inflammation are not fully elucidated.
  • Pyruvate kinase M2 (PKM2), a glycolytic enzyme, possesses non-metabolic roles.

Purpose of the Study:

  • To investigate the role of PKM2 in IL-17-induced keratinocyte signaling and psoriatic inflammation.
  • To explore PKM2 as a potential therapeutic target for psoriasis.

Main Methods:

  • Assessed PKM2 expression in psoriatic skin from patients and mouse models.
  • Utilized genetic depletion of PKM2 in keratinocytes to evaluate its impact on experimental psoriasis.
  • Investigated the molecular complex formation of PKM2 with Act1 and TRAF6.
  • Analyzed the regulation of NF-κB signaling downstream of the IL-17 receptor.

Main Results:

  • PKM2 expression is significantly elevated in the epidermis of psoriatic lesions in both human patients and mouse models.
  • Specific depletion of PKM2 in keratinocytes markedly reduced the development of experimental psoriasis.
  • PKM2 depletion led to decreased production of pro-inflammatory mediators.
  • PKM2 was found to form a complex with Act1 and TRAF6, regulating NF-κB transcriptional signaling.
  • IL-17 was shown to induce PKM2 expression in keratinocytes, creating a positive feedback loop.

Conclusions:

  • PKM2 acts as a key mediator of IL-17A signaling in keratinocytes, driving psoriatic skin inflammation.
  • The interaction of PKM2 with Act1 and TRAF6 is crucial for NF-κB activation in response to IL-17.
  • A positive feedback loop where IL-17 induces PKM2 expression sustains the inflammatory response.
  • PKM2 represents a promising therapeutic target for managing psoriasis.
Keywords:
Act1CP: ImmunologyIL-17ANF-κBPKM2TRAF6inflammationkeratinocytepsoriasisskin

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