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Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.

ABSTRACT: BACKGROUND:Activation of transforming growth factor-?-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury. METHODS:Myeloid TAK1?M and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAo). Brain-infiltrating and splenic immune cells were evaluated at 3 days after stroke. Assessment of infarct size and behavioral deficits were performed on days 3 and 7 post-stroke. RESULTS:Infarcts were significantly smaller in TAK1?M mice (p?

SUBMITTER: Chauhan A

PROVIDER: S-EPMC5960093 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.

Chauhan Anjali A Hudobenko Jacob J Al Mamun Abdullah A Koellhoffer Edward C EC Patrizz Anthony A Ritzel Rodney M RM Ganesh Bhanu P BP McCullough Louise D LD

Journal of neuroinflammation 20180517 1

<h4>Background</h4>Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific ...[more]

PMID: 29776451

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Project description:BackgroundVenous thromboembolism is a major health problem. After thrombus formation, its resolution is essential to re-establish blood flow, which is crucially mediated by infiltrating neutrophils and monocytes in concert with activated platelets and endothelial cells. Thus, we aimed to modulate leukocyte function during thrombus resolution post-thrombus formation by blocking P-selectin/CD62P-mediated cell interactions.MethodsThrombosis was induced by inferior vena cava stenosis through ligation in mice. After 1 day, a P-selectin-blocking antibody or isotype control was administered and thrombus composition and resolution were analyzed.ResultsLocalizing neutrophils and macrophages in thrombotic lesions of wild-type mice revealed that these cells enter the thrombus and vessel wall from the caudal end. Neutrophils were predominantly present 1 day and monocytes/macrophages 3 days after vessel ligation. Blocking P-selectin reduced circulating platelet-neutrophil and platelet-Ly6Chigh monocyte aggregates near the thrombus, and diminished neutrophils and Ly6Chigh macrophages in the cranial thrombus part compared with isotype-treated controls. Depletion of neutrophils 1 day after thrombus initiation did not phenocopy P-selectin inhibition but led to larger thrombi compared with untreated controls. In vitro, P-selectin enhanced human leukocyte function as P-selectin-coated beads increased reactive oxygen species production by neutrophils and tissue factor expression of classical monocytes. Accordingly, P-selectin inhibition reduced oxidative burst in the thrombus and tissue factor expression in the adjacent vessel wall. Moreover, blocking P-selectin reduced thrombus density determined by scanning electron microscopy and increased urokinase-type plasminogen activator levels in the thrombus, which accelerated caudal fibrin degradation from day 3 to day 14. This accelerated thrombus resolution as thrombus volume declined more rapidly after blocking P-selectin.ConclusionsInhibition of P-selectin-dependent activation of monocytes and neutrophils accelerates venous thrombosis resolution due to reduced infiltration and activation of innate immune cells at the site of thrombus formation, which prevents early thrombus stabilization and facilitates fibrinolysis.

Dataset Information

Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.

Publications

Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.

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