microglial-specific depletion of tak1 is neuroprotective in the acute phase after ischemic stroke

Transforming growth factor-β-activated kinase 1 (tak1) is upregulated after cerebral ischemia and contributes to an aggravation of brain injury. tak1 acts as a key regulator of nf-κb and the map kinases jnk and p38 and modulates post-ischemic neuroinflammation and apoptosis. microglia are the main tak1-expressing immunocompetent cells of the brain. however, little is known about the function and regulation of microglial tak1 after cerebral ischemia. tamoxifen-dependent conditional depletion of tak1 in microglial cells was induced in cx3cr1creer-tak1fl/fl mice. the creer-negative tak1fl/fl mice and vehicle-treated (corn oil) mice served as control groups. a transient intraluminal middle cerebral artery occlusion of 30 min followed by 6 h and 72 h of reperfusion was performed in male mice. oxygen-glucose-deprivation (ogd) was performed with primary cortical glial cell cultures to examine the effect of microglial-specific and general (5z-7-oxozeaenol) tak1 inhibition after different reperfusion times (1 h, 6 h, and 72 h). cx3cr1creer-tak1fl/fl mice showed reduced infarct sizes and improved neurological outcomes compared to the control group. the mrna and protein levels of pro-inflammatory il1b/il-1β and tnf/tnf-α in the peri-infarct zones of microglial-specific tak1-depleted mice were significantly reduced. furthermore, tak1 depletion in vitro led to reduced cell death rates after ogd. moreover, hypoxia-mediated activation of tak1 and its downstream signalling proteins, jnk and p38, were dampened by microglial tak1 depletion. in contrast, 5z-7-oxozeaenol-induced pharmacological inhibition of tak1 completely diminished mapk-signalling including the kinases jnk and p38 in all cells. microglial tak1 depletion abrogates post-ischemic neuroinflammation and apoptosis in the acute phase, hence might be considered as a potential target in the treatment of cerebral hypoxia.