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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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39 hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39 hi plasmablasts and adenosine accumulation. Our study reveals CD39 hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)