Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury
Wen-Hai Chou, Doo-Sup Choi, Hong Zhang, Dezhi Mu, Tom McMahon, Viktor N. Kharazia, Clifford A. Lowell, Donna M. Ferriero, Robert O. Messing
Wen-Hai Chou, Doo-Sup Choi, Hong Zhang, Dezhi Mu, Tom McMahon, Viktor N. Kharazia, Clifford A. Lowell, Donna M. Ferriero, Robert O. Messing
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Article Neuroscience

Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury

Abstract

Thrombolysis is widely used to intervene in acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Here we describe studies with mice lacking protein kinase Cδ (PKCδ) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue and with impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. Total body irradiation followed by transplantation with bone marrow from PKCδ-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCδ-null mice. These results indicate an important role for neutrophil PKCδ in reperfusion injury and strongly suggest that PKCδ inhibitors could prove useful in the treatment of stroke.

Authors

Wen-Hai Chou, Doo-Sup Choi, Hong Zhang, Dezhi Mu, Tom McMahon, Viktor N. Kharazia, Clifford A. Lowell, Donna M. Ferriero, Robert O. Messing

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Expression pattern of PKCδ in the brain and extravascular neutrophils af...
Expression pattern of PKCδ in the brain and extravascular neutrophils after transient MCA occlusion. (A and B) Immunocytochemical localizations of PKCδ in the mouse brain are shown in coronal sections at bregma 0.38 mm (A) and a more posterior section at bregma –1.58 mm (B) for PKCδ+/+ (left) and PKCδ –/ – (right) mice. (C) Representative sections from PKCδ+/+ and PKCδ –/ – mice showing reduced neutrophil accumulation within infarcted tissue in the cortex of PKCδ –/ – mice after 1 hour of MCAO and 24 hours of reperfusion. Blue infiltrated neutrophils were identified in the ischemic cortex by staining for esterase activity with dichloroacetate (arrows). (D and E) Number of extravascular neutrophils in the ischemic cortex and striatum of PKCδ+/+ (n = 7) and PKCδ –/ – mice (n = 6) after transient MCAO. No esterase staining was seen in sections from nonischemic animals (data not shown). The scale bars in A and C correspond to 1 mm and 25 & μ;m, respectively. *P < 0.05 compared with WT littermates.