Inhibiting protein kinase activity of pyruvate kinase M2 by sirtuin 2 deacetylase attenuates psoriasis.

Abstract Signal transducer and activator of transcription 3 (STAT3) is crucial for the pathogenesis of psoriasis. Studies describe pleiotropic roles for a glycolytic enzyme pyruvate kinase M2 (PKM2) as a nuclear kinase of STAT3. However, little is known about the function of PKM2 in Th17 cells in association with STAT3. In this study, we investigated whether and how sirtuin 2 (Sirt2) deacetylase regulated the protein kinase function of PKM2 in Th17 cell-mediated inflammatory responses in psoriasis. Sirt2 KO mice and WT littermates had psoriatic dermatitis induced by topical treatment of imiquimod or intradermal injection of recombinant IL-23. An initial downregulation of Sirt2 and increase in PKM2 acetylation and STAT3 phosphorylation were observed in psoriasiform lesions of mice. Sirt2 directly interacted with and deacetylated PKM2 to suppress STAT3 phosphorylation. Consequently, psoriasiform skin inflammation was aggravated in Sirt2 KO mice. Conversely, genetic re-expression of Sirt2 or pharmacological blockade of PKM2 decreased disease severity. Flow cytometric analysis of skin tissues of Sirt2 KO mice showed enhanced infiltration of Th17 cells. Ex vivo experiments showed that Sirt2 deficiency accelerated Th17 cell differentiation with concomitant production of IL-17A and IL-22. The results suggest Sirt2-mediated PKM2 deacetylation as an effective option for psoriasis therapy.