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Orchestrating the frontline: HDAC3-miKO recruits macrophage reinforcements for accelerated myelin debris clearance
Jiaying Li1, Chenran Wang1, Yue Zhang1
1State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China.
Abstract:
Rational: White matter has emerged as a key therapeutic target in ischemic stroke due to its role in sensorimotor and cognitive outcomes. Our recent findings have preliminarily revealed a potential link between microglial HDAC3 and white matter injury following stroke. However, the mechanisms by which microglial HDAC3 mediates these effects remain unclear. Methods : We generated microglia-specific HDAC3 knockout mice (HDAC3-miKO). DTI, electrophysiological technique and transmission electron microscopy were used to assess HDAC3-miKO's effects on white matter. RNA sequencing, flow cytometry, immunofluorescence staining and ex vivo phagocytosis assay were conducted to investigate the mechanism by which HDAC3-miKO ameliorated white matter injury. Macrophage depletion and reconstitution experiments further confirmed the involvement of macrophage CCR2 in the enhanced white matter repair and sensorimotor function in HDAC3-miKO mice. Results : HDAC3-miKO promoted post-stroke oligodendrogenesis and long-term histological and functional integrity of white matter without affecting early-stage white matter integrity. In the acute phase, HDAC3-deficient microglia showed enhanced chemotaxis, recruiting macrophages to the infarct core probably by CCL2/CCL7, where dMBP-labelled myelin debris surged and coincided with their infiltration. Infiltrated macrophages outperformed resident microglia in myelin phagocytosis, potentially serving as true pioneers in myelin debris clearance. Although macrophage phagocytosis potential was similar between HDAC3-miKO and WT mice, increased macrophage numbers in HDAC3-miKO accelerated myelin debris clearance. Reconstitution with CCR2-KO macrophages in HDAC3-miKO mice slowed this clearance, reversing HDAC3-miKO's beneficial effects. Conclusions : Our study demonstrates that HDAC3-deficient microglia promote post-stroke remyelination by recruiting macrophages to accelerate myelin debris clearance, underscoring the essential role of infiltrated macrophages in HDAC3-miKO-induced beneficial outcomes. These findings advance our understanding of microglial HDAC3's role and suggest therapeutic potential for targeting microglial HDAC3 in ischemic stroke.
Insights
Targeting microglial HDAC3 (Histone Deacetylase 3) in ischemic stroke promotes white matter repair. This involves recruiting macrophages to clear myelin debris, enhancing remyelination and sensorimotor function.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- White matter integrity is crucial for sensorimotor and cognitive functions after ischemic stroke.
- Microglial Histone Deacetylase 3 (HDAC3) has been preliminarily linked to white matter injury, but its precise role and mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of microglial HDAC3 in white matter injury following ischemic stroke.
- To elucidate the mechanisms by which modulating microglial HDAC3 affects white matter repair and functional recovery.
Main Methods:
- Generation of microglia-specific HDAC3 knockout (HDAC3-miKO) mice.
- Assessment of white matter integrity using diffusion tensor imaging (DTI), electrophysiology, and electron microscopy.
- Investigation of molecular mechanisms via RNA sequencing, flow cytometry, immunofluorescence, and phagocytosis assays.
- Confirmation of macrophage involvement using depletion and reconstitution experiments with CCR2 knockout (CCR2-KO) macrophages.
Main Results:
- HDAC3-miKO mice exhibited improved long-term white matter integrity, oligodendrogenesis, and sensorimotor function post-stroke.
- HDAC3-deficient microglia enhanced macrophage recruitment to the infarct core, likely via CCL2/CCL7, accelerating myelin debris clearance.
- Infiltrated macrophages, rather than resident microglia, were key drivers of enhanced myelin phagocytosis.
- CCR2-mediated macrophage recruitment was essential for the beneficial effects observed in HDAC3-miKO mice.
Conclusions:
- Microglial HDAC3 deficiency promotes post-stroke white matter repair by recruiting macrophages to expedite myelin debris clearance.
- Infiltrated macrophages play a critical role in the therapeutic benefits of targeting microglial HDAC3.
- Targeting microglial HDAC3 represents a potential therapeutic strategy for ischemic stroke to improve white matter outcomes.
