Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation

Abstract

Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.

The Relapse of Psoriasis: Mechanisms and Mysteries

“…Particularly, glucose metabolism has been shown to selectively involved in keratinocyte hyperproliferation in lesional skin of individuals with psoriasis (Zhang et al, 2018). We (unpublished data) and other groups also found that glycolysis pathway and amino acid metabolic activity were upregulated in lesional skin and serum from patients with psoriasis, and lactic acid is a major glycolytic metabolite elevated in psoriatic lesions (Cibrian et al, 2020, Kang et al, 2017, Liu et al, 2021. Lactic acid has been shown to promote acetylation of histone lysine residues by inhibiting histone deacetylases and stimulate gene transcription from chromatin (Latham et al, 2012).…”

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

“…Furthermore, topical application of GLUT inhibitor WZB117 attenuated both posriasiform hyperplasia and inflammation in mouse models of psoriasis, identifying glucose transport as a promising therapeutic target of psoriasis [ 59 ]. Also, suppressing glucose metabolism by 2-deoxy-d-glucose (2DG), a glucose analog, inhibited keratinocyte proliferation and alleviated IMQ-induced skin lesions [ 58 , 60 , 61 ]. Glycolysis and aerobic respiration are also related with keratinocyte function in psoriasis.…”

“…Moreover, genetic deletion of PKM2 in keratinocytes or pharmacological inhibition of PKM2 markedly reduced psoriasis-like skin lesions induced by IMQ. Importantly, EGF may contribute to the induction of PKM2 in keratinocyte through ERK1/2 pathway [ 61 ].…”

Construction of Glucose-6-Phosphate Dehydrogenase Overexpression Strain of Schizochytrium sp. H016 to Improve Docosahexaenoic Acid Production

“…Increase in PK expression level may accelerate the accumulation of acetyl-CoA, which provides a large amount of reaction substrate for fatty acid production. The overexpression of PK promotes keratinocyte glycolytic metabolism, whereas the downregulation of PK inhibits keratinocyte proliferation and glycolysis [ 47 ].…”