Microglia/macrophages (Mi/M) can profoundly influence stroke outcomes by acquiring functionally dominant phenotypes (pro-inflammatory or anti-inflammatory; neurotoxic or neuroprotective). Identification of the molecular mechanisms that dictate the functional status of Mi/M after brain ischemia/reperfusion may reveal novel therapeutic targets for stroke. We hypothesized that activation of TGF-activated kinase 1 (TAK1), a key MAP3K upstream of multiple inflammation-regulating pathways, drives Mi/M towards a pro-inflammatory phenotype and potentiates ischemia/reperfusion brain injury. Young adult mice were subjected to 1 h of middle cerebral artery occlusion (MCAO) followed by reperfusion. TAK1 was targeted by tamoxifen-induced Mi/M-specific knockout (mKO).  Mi/M functional status and brain inflammatory profiles were assessed 3 days after MCAO by RNA-seq of flow cytometry-sorted brain Mi/M. The results showed that TAK1 promotes ischemia/reperfusion-induced inflammation, brain injury, and maladaptive behavior by enhancing pro-inflammatory and neurotoxic Mi/M responses. SOURCE: Yejie Shi (y.shi@pitt.edu) -  University of Pittsburgh

Pluto Bioinformatics

GSE141972: TGF-activated kinase 1-dependent microglial and macrophage responses aggravate long-term outcomes after ischemic stroke