RGD Reference Report - Transforming Growth Factor Beta-Activated Kinase 1-Dependent Microglial and Macrophage Responses Aggravate Long-Term Outcomes After Ischemic Stroke. - Rat Genome Database

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Transforming Growth Factor Beta-Activated Kinase 1-Dependent Microglial and Macrophage Responses Aggravate Long-Term Outcomes After Ischemic Stroke.

Authors: Wang, Rongrong  Pu, Hongjian  Ye, Qing  Jiang, Ming  Chen, Jie  Zhao, Jingyan  Li, Sicheng  Liu, Yaan  Hu, Xiaoming  Rocha, Marcelo  Jadhav, Ashutosh P  Chen, Jun  Shi, Yejie 
Citation: Wang R, etal., Stroke. 2020 Mar;51(3):975-985. doi: 10.1161/STROKEAHA.119.028398. Epub 2020 Feb 12.
RGD ID: 155791642
Pubmed: PMID:32078472   (View Abstract at PubMed)
DOI: DOI:10.1161/STROKEAHA.119.028398   (Journal Full-text)

Background and Purpose- Microglia/macrophages (Mi/MΦ) can profoundly influence stroke outcomes by acquiring functionally dominant phenotypes (proinflammatory or anti-inflammatory; deleterious or salutary). Identification of the molecular mechanisms that dictate the functional status of Mi/MΦ after brain ischemia/reperfusion may reveal novel therapeutic targets for stroke. We hypothesized that activation of TAK1 (transforming growth factor beta-activated kinase 1), a key MAP3K upstream of multiple inflammation-regulating pathways, drives Mi/MΦ toward a proinflammatory phenotype and potentiates ischemia/reperfusion brain injury. Methods- Young adult mice were subjected to 1 hour of middle cerebral artery occlusion (MCAO) followed by reperfusion. TAK1 was targeted by tamoxifen-induced Mi/MΦ-specific knockout or administration of a selective inhibitor 5Z-7-Oxozeaenol after MCAO. Neurobehavioral deficits and long-term gray matter and white matter injury were assessed up to 35 days after MCAO. Mi/MΦ functional status and brain inflammatory profiles were assessed 3 days after MCAO by RNA-seq, flow cytometry, and immunohistochemistry. Results- TAK1 Mi/MΦ-specific knockout markedly ameliorated neurological deficits in the rotarod and cylinder tests for at least 35 days after MCAO. Mechanistically, RNA-seq of purified brain Mi/MΦ demonstrated that proinflammatory genes and their predicted biological functions were downregulated or inhibited in microglia and macrophages from TAK1 Mi/MΦ-specific knockout mice versus WT mice 3 days after MCAO. Consistent with the anti-inflammatory phenotype of Mi/MΦ-specific knockout, oxozeaenol treatment mitigated neuroinflammation 3 days after MCAO, manifested by less Iba1+/CD16+ proinflammatory Mi/MΦ and suppressed brain invasion of various peripheral immune cells. Oxozeaenol treatment beginning 2 hours after MCAO improved long-term sensorimotor and cognitive functions in the foot fault, rotarod, and water maze tests. Furthermore, Oxozeaenol promoted both gray matter and white matter integrity 35 days after MCAO. Conclusions- TAK1 promotes ischemia/reperfusion-induced inflammation, brain injury, and maladaptive behavior by enhancing proinflammatory and deleterious Mi/MΦ responses. Therefore, TAK1 inhibition is a promising therapy to improve long-term stroke outcomes.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
transient cerebral ischemia amelioratesISOMap3k7 (Mus musculus)155791642; 155791642 RGD 
transient cerebral ischemia amelioratesIMP 155791642 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k7  (mitogen activated protein kinase kinase kinase 7)

Genes (Mus musculus)
Map3k7  (mitogen-activated protein kinase kinase kinase 7)

Genes (Homo sapiens)
MAP3K7  (mitogen-activated protein kinase kinase kinase 7)


Additional Information