Myeloid HDAC3 Deletion Protects Against Traumatic Optic Injury

Background Traumatic optic neuropathy (TON) occurs due to trauma to the optic nerve, resulting in blindness. Current management focuses primarily on supportive care, highlighting an urgent need to identify novel treatment targets. Neuronal expression of the enzyme histone deacetylase 3 (HDAC3) has been previously implicated in retinal ganglion cell (RGC) degeneration after optic nerve crush (ONC) a model of TON. Here we investigated the role of myeloid HDAC3 (i.e. HDAC3 expressed in microglia and macrophages) in RGC loss, axonal degeneration and efferocytosis, a reparative process by which phagocytic myeloid cells engulf apoptotic cells. Methods ONC injury was performed on myeloid-specific HDAC3 knockout (KO) and floxed control mice. Retinal flatmounts were isolated and stained for an in vivo efferocytosis assay, and neurodegeneration was assessed by confocal imaging. RGC function was evaluated using pattern electroretinography. Axonal sprouting was quantified by anterograde transport of cholera toxin B injection. Myelin debris clearance assay was performed in vitro using bone marrow-derived macrophages isolated from HDAC3 KO and control mice. Results Myeloid-HDAC3 deletion preserved RGC and improved axonal regeneration after ONC, together with improved retinal function. Furthermore, the Deletion of HDAC3 enhanced the phagocytic function of myeloid cells to effectively remove apoptotic cells and myelin debris, both in vivo and in vitro, by increasing the expression of the tyrosine kinase receptor, MerTK. Conclusions The deletion of myeloid-HDAC3 enhances efferocytosis, leading to neuroprotection and functional recovery following ONC. Targeting myeloid-HDAC3 presents a novel therapeutic strategy for TON.