Pyruvate Kinase Isoenzyme M2 Impairs Cognition in Systemic Lupus Erythematosus by Promoting Microglial Synaptic Pruning via β-Catenin Signaling Pathway

Abstract

Background Neuropsychiatric systemic lupus erythematosus (NPSLE) is the severest complication of SLE, which often involves pathological damage to the brain and cognitive function. Glucose metabolic changes are observed in SLE patients with cognitive impairments by medical imaging. Pyruvate kinase isoform M2 (PKM2) is a vital catalyzer of glucose catabolic pathways and in neurological diseases. However, PKM2 regarding the progress of NPSLE remains poorly studied. Thus, this study aimed to analyze and compare the central carbon metabolites in the validated neuropsychiatric lupus model and control mice. Methods MRL/Mp-Faslpr (MRL/lpr) female mice were used as NPSLE mouse model, C57BL6 as control. Metabolomics to assess hippocampa glycolysis level. Glucose, lactic acid, IL-6 and IL-1β of hippocampal were detected by ELISA. The expression of PKM2 was detected by qRT-PCR and western blotting, and the localization of PKM2 in microglia and neurons was assessed with IBA-1, NeuN and PKM2 immunohistochemistry. Flow cytometry was used to detect the number and phenotype of microglia. In vitro, after transfected PKM2 overexpression plasmid on BV2, the effect on microglia and β-catenin signaling pathway were detected. Finally, PKM2 inhibitor Shikonin was injected into MRL/lpr mice, behavioral testing were performed to assess cognition, HE and FJB staining were used to evaluate brain damage.Results Glycolysis was elevated in the hippocampal tissues from MRL/lpr lupus mice, accompanied by an increase in glucose consumption and lactate production. Based on these metabolic variations, PKM2 activation was revealed in hippocampal microglia from lupus mice. Furthermore, PKM2 facilitated microglial phagocytic activity and engulfment of neurons via β-catenin signaling. In vivo, an inhibitor of PKM2, Shikonin, was shown to reduce microglial activation, loss of neuronal synapses, and block β-catenin signaling. Accordingly, the cognitive impairment and brain damage of MRL/lpr mice were relieved. Conclusion These results indicated that abnormal glycolytic metabolism in the brain tissue of NPSLE mice was induced by PKM2 overexpression, which increased the activation of microglia and the ability of phagocytizing neuronal synapses, leading to neuronal loss and cognitive dysfunction in lupus. These phenomena indicated that inhibition on PKM2 would be a novel therapeutic target for the treatment of lupus encephalopathy.