Microglia play a complex role in the response to brain injury, with past work showing that these cells can both aid in the recovery from ischemic stroke and exacerbate its pathology. A recent study in Science Advances explores this topic through the chromatin remodeling protein HDAC3, which broadly activates the expression of target genes. The authors surgically induced transient focal cerebral ischemia (tFCI) in wild-type mice and in mice in which Cre–lox recombination enabled selective depletion of Hdac3 in microglia. Mice lacking microglial Hdac3 developed less severe brain lesions and white matter damage and experienced faster motor recovery from tFCI compared to wild-type littermates. Depletion of microglial Hdac3 also limited the emergence of pro-inflammatory CD16+ microglia after tFCI without affecting the proliferation of other, anti-inflammatory, microglia. A multi-omic analysis revealed that predicted targets of the transcription factor PU.1 were dysregulated following loss of microglial Hdac3 in mice that underwent tFCI. Consequently, overexpression of PU.1 in Hdac3-lacking microglia partly restored the proliferation of CD16+ microglia. Overall, these findings suggest a pathway by which stroke induces HDAC3-mediated chromatin remodeling, thereby activating PU.1 and the rise of pro-inflammatory microglia that complicate recovery from brain injury.

Original reference: Sci. Adv. 10, eade6900 (2024)