PKM2-mediated metabolic reprogramming of microglia in neuroinflammation

Abstract

Microglia, the resident immune cells of the central nervous system, undergo metabolic reprogramming during neuroinflammation, playing a crucial role in the pathogenesis of neurological disorders such as Parkinson's disease. This review focuses on Pyruvate Kinase M2 (PKM2), a key glycolytic enzyme, and its impact on microglial metabolic reprogramming and subsequent neuroinflammation. We explore the regulatory mechanisms governing PKM2 activity, its influence on microglial activation and immune responses, and its contribution to the progression of various neurological diseases. Finally, we highlight the therapeutic potential of targeting PKM2 as a novel strategy for treating neuroinflammation-driven neurological disorders. This review provides insights into the molecular mechanisms of PKM2 in neuroinflammation, aiming to inform the development of future therapeutic interventions.

Fig. 1. Expression of pyruvate kinase isoforms.

Mammals express four pyruvate kinase isoforms: PKL, PKR, PKM1, and PKM2, encoded by two PK genes. One gene encodes PKL and PKR, sharing exons 3-12. PKR transcripts retain exon 1 and are predominantly expressed in red blood cells. PKL transcripts retain exon 2 and are primarily expressed in the liver, kidney, pancreas, and intestine. The other gene encodes PKM1 and PKM2, sharing exons 1-8 and 11-12. PKM1 transcripts retain exon 9 and are expressed in differentiated tissues such as the heart, brain, kidney, and muscle. PKM2 transcripts retain exon 10 and are expressed in brain, lung, liver, kidney, heart, embryonic tissues, and tumor cells. PKM2 expression is significantly upregulated during inflammation.

Fig. 2. PKM2 and microglial immune status.

During neuroinflammation, upregulated PKM2 in microglia drives metabolic reprogramming, inducing pro-inflammatory (M1) polarization and chemotaxis. Enhanced glycolytic acid production in astrocytes and neurons exhibits dual effects: promoting neuronal activity at physiological levels while exacerbating inflammatory cascades when overaccumulated. PKM2 inhibition reverses this metabolic shift by augmenting oxidative phosphorylation, thereby triggering an anti-inflammatory (M2) phenotypic transition that confers neuroprotection.

Fig. 3. Regulation of PKM2.

Under physiological conditions, cytoplasmic PKM2 exists as a tetramer. Upon microglia activation, PKM2 dissociates into dimers and translocates to the nucleus to regulate gene expression. HIF-1α directly upregulates PKM2 expression and its nuclear translocation. In the nucleus, PKM2 phosphorylates HIF-1α, forming a complex that promotes IL-1β secretion. Additionally, PKM2 phosphorylates STAT3 to enhance the release of IL-6/IL-1β, thereby exacerbating the inflammatory response. Moreover, PKM2 interacts with signaling pathways such as ATF2, Pyk2, β-catenin, and mTOR to regulate its own expression, glycolysis, and microglial polarization within pro-inflammatory environments.