Inhibiting H3K18 lactylation in microglia aggravates white matter injury after intracerebral hemorrhage in mice.

Abstract

BACKGROUND: White matter injury (WMI) is a key contributor to long-term cognitive deficits following intracerebral hemorrhage (ICH), yet its underlying mechanisms remain incompletely understood. AIMS: This study aims to investigate the role of histone H3K18 lactylation (H3K18la) and microglial function in post-ICH WMI and cognitive impairment. METHODS: Utilizing a collagenase-induced ICH mouse model, we assessed H3K18la expression dynamics (days 3, 7, 14, 21 post-ICH) and the effects of inhibiting lactate dehydrogenase (using Oxamate) or p300/CBP histone acetyltransferase (using A-485) on WMI and cognitive function. Furthermore, we employed PLX5622 (a colony-stimulating factor 1 receptor inhibitor) to deplete microglia (MG), alone or combined with A-485, to examine the role of p300/CBP inhibition in the context of MG absence. WMI was evaluated using myelin basic protein (MBP), neurofilament H (non-phosphorylated; SMI32) immunostaining, and transmission electron microscopy. Oligodendrocyte precursor cell (OPC) accumulation around the hematoma was quantified, and microglial depletion was verified by cell counting. Cognitive function was assessed up to 28 days post-ICH using the Morris Water Maze test. RESULTS: H3K18la levels were elevated and oligodendrocyte precursor cells (OPCs) increased in the perihematomal region post-ICH. A-485 administration significantly reduced microglial H3K18la, concomitantly suppressed OPC recruitment to the injury site, and exacerbated both WMI and long-term cognitive impairment. In contrast, oxamate administration did not significantly reduce microglial H3K18la or exacerbate cognitive deficits, but it did significantly aggravate WMI. PLX5622-induced MG depletion similarly aggravated WMI and cognitive deficits. However, combined PLX5622 and A-485 treatment did not produce additive worsening compared to MG depletion alone. CONCLUSION: These results demonstrated that lactate-derived H3K18 lactylation (H3K18la), orchestrated by p300/CBP-mediated epigenetic reprogramming, serves as a critical endogenous neuroprotective axis of WMI following ICH. Microglia emerge as the cellular executors of this pathway. This lactate-p300/CBP-H3K18la axis thus represents a therapeutically targetable mechanism for enhancing post-hemorrhagic brain repair through microglia-guided myelin regeneration.