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Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation.

Gelderblom M, Neumann M, Ludewig P, Bernreuther C, Krasemann S, Arunachalam P, Gerloff C, Glatzel M, Magnus T - PLoS ONE (2013)

Bottom Line: Not only reperfusion but also tPA itself can induce an inflammatory response.Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia.This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

ABSTRACT
The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.

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Activation of microglia is increased in the absence of neuroserpin.(A) Frequency of TNF-α positive brain microglia in wt and Ns−/− mice analyzed by flow cytometry three days after stroke. Representative dot plots show CD11b+ CD45intermediate-gated microglia. The graphs show means±SD of 9–12 animals per group analyzed three days after MCAO in three or four independent experiments. t test was used to assess statistical significance. (B) Immunohistochemical analysis of TNF-αexpression in ischemic hemispheres 3 days following 1 h MCAO showing an increased TNF-α immunoreactivity in ischemic tissue from Ns−/− mice compared to wt mice (scale bar = 50 µm).
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pone-0063118-g004: Activation of microglia is increased in the absence of neuroserpin.(A) Frequency of TNF-α positive brain microglia in wt and Ns−/− mice analyzed by flow cytometry three days after stroke. Representative dot plots show CD11b+ CD45intermediate-gated microglia. The graphs show means±SD of 9–12 animals per group analyzed three days after MCAO in three or four independent experiments. t test was used to assess statistical significance. (B) Immunohistochemical analysis of TNF-αexpression in ischemic hemispheres 3 days following 1 h MCAO showing an increased TNF-α immunoreactivity in ischemic tissue from Ns−/− mice compared to wt mice (scale bar = 50 µm).

Mentions: We used TNF-α expression of microglia to determine microglial activation. While in wt mice 35.0±7.0% of the microglia were positive for TNF-α the amount of microglia producing TNF-α in Ns−/− mice was significant increased to 59.3±8.7% (Fig. 4A). The increased TNF-αlevels in Ns−/− mice could be confirmed in immunohistochemical studies, showing an increased abundance of TNF-α positive cells with microglial morphology in Ns−/− compared to wt mice (Fig. 4B).


Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation.

Gelderblom M, Neumann M, Ludewig P, Bernreuther C, Krasemann S, Arunachalam P, Gerloff C, Glatzel M, Magnus T - PLoS ONE (2013)

Activation of microglia is increased in the absence of neuroserpin.(A) Frequency of TNF-α positive brain microglia in wt and Ns−/− mice analyzed by flow cytometry three days after stroke. Representative dot plots show CD11b+ CD45intermediate-gated microglia. The graphs show means±SD of 9–12 animals per group analyzed three days after MCAO in three or four independent experiments. t test was used to assess statistical significance. (B) Immunohistochemical analysis of TNF-αexpression in ischemic hemispheres 3 days following 1 h MCAO showing an increased TNF-α immunoreactivity in ischemic tissue from Ns−/− mice compared to wt mice (scale bar = 50 µm).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643909&req=5

pone-0063118-g004: Activation of microglia is increased in the absence of neuroserpin.(A) Frequency of TNF-α positive brain microglia in wt and Ns−/− mice analyzed by flow cytometry three days after stroke. Representative dot plots show CD11b+ CD45intermediate-gated microglia. The graphs show means±SD of 9–12 animals per group analyzed three days after MCAO in three or four independent experiments. t test was used to assess statistical significance. (B) Immunohistochemical analysis of TNF-αexpression in ischemic hemispheres 3 days following 1 h MCAO showing an increased TNF-α immunoreactivity in ischemic tissue from Ns−/− mice compared to wt mice (scale bar = 50 µm).
Mentions: We used TNF-α expression of microglia to determine microglial activation. While in wt mice 35.0±7.0% of the microglia were positive for TNF-α the amount of microglia producing TNF-α in Ns−/− mice was significant increased to 59.3±8.7% (Fig. 4A). The increased TNF-αlevels in Ns−/− mice could be confirmed in immunohistochemical studies, showing an increased abundance of TNF-α positive cells with microglial morphology in Ns−/− compared to wt mice (Fig. 4B).

Bottom Line: Not only reperfusion but also tPA itself can induce an inflammatory response.Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia.This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

ABSTRACT
The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.

Show MeSH
Related in: MedlinePlus