Microglial-specific depletion of TAK1 is neuroprotective in the acute phase after ischemic stroke

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 messages TAK1 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.

Erythropoietin Abrogates Post-Ischemic Activation of the NLRP3, NLRC4, and AIM2 Inflammasomes in Microglia/Macrophages in a TAK1-Dependent Manner

“…The latter are regulated by the mitogen-activated protein kinase kinase kinase (MAP3K) TGFβ-activated kinase 1 (TAK1). TAK1 is highly abundant in the brain and predominantly expressed in microglial cells [20]. It controls viability and inflammation through multiple downstream effectors including MAP kinases p38 and JNK, as well as the transcription factor NF-κB [21][22][23][24].…”

“…It controls viability and inflammation through multiple downstream effectors including MAP kinases p38 and JNK, as well as the transcription factor NF-κB [21][22][23][24]. Various stimuli including Toll-like receptor 4 (TLR4), TNF-α, IL-1β as well as hypoxia/ischemia have been shown to upregulate and activate TAK1 [20,23,25,26]. While activation of TAK1 is reported to exacerbate brain damage, pharmacological inhibition of TAK1 using 5Z-7-Oxozeaenol exerts neuroprotection after subarachnoid hemorrhage as well as cerebral ischemia [23,25,26].…”

“…We have recently demonstrated that the deletion of microglial and macrophage (Mi/MΦ) TAK1 significantly reduced infarct sizes, neurological impairments, as well as the levels of TNF-α, IL-1β, and IL-6 in the periinfarct zone after transient middle cerebral artery occlusion (tMCAo) [20]. Although several cytokines are implicated in post-ischemic inflammation, a crucial role is particularly played by IL-1β.…”

A panel of two miRNAs correlated to systolic blood pressure is a good diagnostic indicator for stroke

“…TGF-β, a cytokine with multiple functions, regulates inflammatory response following injury in the brain [ 43 ]. Meanwhile, TGF-β activated kinase 1 (TAK1) correlates with the aggravation of injury [ 44 ], and contributes to an inferior long-term stroke outcome via microglial and macrophage responses [ 45 ]. Additionally, PPI with target genes of 67 hub DE-miRNAs emphasized eleven hub genes, i.e., CDC27, SMURF1, RPS21, AREL1, BTBD6, FBXO9, KLHL25, PIK3CB, TRIM71, UBE2R2, and ZNRF2.…”

Neuroprotective Effects of Alisol A 24-acetate on Cerebral Ischemia-reperfusion Injury by Regulating PI3K/AKT Pathway

“…Studies have shown that microglia plays a pro-in ammatory and pro-apoptotic role in the early stage of I/R [16], which regulating immune response and affecting neuronal function. Microglia works in the early stage of ischemia-reperfusion through morphological changes and secretion of in ammatory factors [17].…”