Objective: This study aims to investigate the role of histone lactylation in microglia-mediated neuroinflammation and dopaminergic (DA) neuronal damage in Parkinson’s disease (PD).
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Background: Augmented glycolysis induced by metabolic reprogramming (Warburg effect) is involved in microglia polarization and the pathogenesis of PD. Lactate, an primary end point of Warburg effect has been recently verfied to modify histones lactylation (Kla), a novel post-translational modification. Kla was showed to promote gene expression linked to tissue repair during M1 macrophage polarization. However, the role of Kla in microglia-mediated neuroinflammation remains unclear.

Method: Glycolysis and oxidative phosphorylation in MPTP-induced PD mouse model and LPS-induced neuroinflammation were assessed by Seahorse XFe24. Chip-seq was used to analyze H3K9la specific enrichment gene promoter regions and their potential signaling pathways.C646 and siRNA were used to inhibit the activity and expression of acetylases p300/CBP.

Results: We showed that lactate was markedly increased in the conditioned media of α-synclein-inducded M1 microglia polarization and in substantia nigra and striatum from mice with MPTP. 2-Deoxy-D-glucose (2-DG) or 3-Bromopyruvic acid (3-BPA) or oxamate inhibited LPS-induced microglia-mediated inflammatory response. Moreover, intraperitoneal injection of 2-DG or 3-BPA restored motor function and reduced M1 microglia polarization and dopamine neuron death in MPTP mice. Mechanistically, lactate induced H3K9 lactylation (H3K9la) in the promoters of NLRP3 inflammasome and up-regulation its downstream caspase-1 pathway. Lactate induced H3K9la may be mediated by the acetylases p300/CBP, as demonstrated by the reduced levels of H3K9la and NLRP3 inflammasome after p300/CBP knockdown in microglia.

Conclusion: Our results revealed the regulatory role of H3K9la in microglia-mediated neuroinflammation, thus providing novel immunotherapy targets for PD. We linked energy metabolism reprogramming to microglial immune function, providing new insights into metabolite regulation of epigenetics in PD development.

References: [1] Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575-80.
[2] Irizarry-Caro RA, McDaniel MM, Overcast GR, et al. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc Natl Acad Sci U S A. 2020;117(48):30628-38.
[3] Hagihara H, Shoji H, Otabi H, et al. Protein lactylation induced by neural excitation. Cell reports. 2021;37(2):109820.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/aerobic-glycolysis-regulates-microglia-mediated-neuroinflammation-by-promoting-h3k9-lactylation-in-parkinsons-disease/