Abstract
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.Key messagesTAK1 is activated after cerebral ischemia and induces MAP kinases p38 and JNK.Activated TAK1 increases apoptosis rate and the level pro-inflammatory cytokines IL-1β and TNF-α.Microglial cells seem to be the main source of TAK1-mediated post-ischemic neuroinflammation.Microglial-specific TAK1-depletion mediates sustainable neuroprotective effects, which might be superior to global TAK1 inhibition.
Highlights
Ischemic stroke is one of the major causes of death and longterm disability in adults in most developed countries [1, 2]
Microglial-specific depletion of transforming growth factor-β-activated kinase 1 (TAK1) resulted in reduced infarct sizes and attenuated neurological deficits after transient intraluminal middle cerebral artery occlusion (tMCAo)
Previous studies have shown that TAK1 activation occurs after brain injury [20, 29]
Summary
Ischemic stroke is one of the major causes of death and longterm disability in adults in most developed countries [1, 2]. Cerebral ischemia causes necrotic cell death in the infarct core, and delayed apoptosis in the adjacent penumbra region. The latter is amenable to therapeutic strategies [3,4,5]. The post-ischemic injury initiates a cascade of inflammatory and pro-apoptotic events, which aggravate the damage and in turn determine the recovery after stroke [6, 7]. NF-ΚB and the MAP kinases JNK and p38 are major regulators of pro-inflammatory gene transcription [10,11,12,13]. An excessive production of the latter activates inflammatory and apoptotic signalling in the brain resulting in progressive tissue damage [19, 20]
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