Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway

• DOI: 10.3390/brainsci13020262
• Publication Date: 2023-02-06T07:29:23Z
• Authors: Xinlin Li; Rong Zhou; Hui Peng; Jing Peng; Qiaoling Li; Meng Mei
• Keywords: 0301 basic medicine; 03 medical and health sciences; neural network; epilepsy; Neurosciences. Biological psychiatry. Neuropsychiatry; C3; PKM2; Article; neuroinflammation; RC321-571; 3. Good health

Epilepsy is a neurological disease and approximately 30% of patients have failed to respond to current anti-epilepsy drugs. The neuroinflammation mechanism has raised increasing concerns and been regarded as the novel treatment strategy in epilepsy, but the target molecules require further research. Pyruvate kinase isoform 2 (PKM2) is well studied in peripheral inflammation, but its role in epilepsy neuroinflammation remains unclear. We knocked down microglia PKM2 in the hippocampus using a stereotaxic adeno-associated virus (AAV) microinjection and established a pilocarpine-induced status epilepticus (PISE) model. Racine score was used to evaluate the seizure grade. Next, we used WB, Multiplex tyramide signal amplification (TSA) staining and other methods to determine neuroinflammation and the complement component 3 (C3)–C3aR interaction in primary microglia. Results showed that microglia PKM2 knockdown reduced epilepsy grade and rescued neuron loss. Mechanistically, PKM2 knockdown inhibited microglia activation and inflammation factor secretion through suppressing p65 expression and phosphorylation. The reduced microglia C1q, TNF-α, and IL-1α were responsible for the decreased astrocyte C3 expression and the following neuron damage caused by the C3–C3aR interaction. Our data suggest that microglia PKM2 inhibition ameliorates neuroinflammation and neuron loss through C3-C3aR interaction in epilepsy, which provides an attractive target for the intervention of damaged neuron-glia crosstalk in epilepsy.