Genetic neutrophil deficiency ameliorates cerebral ischemia-reperfusion injury

Abstract

Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Myeloid Mcl1 knockout mice were subjected to transient middle cerebral artery occlusion and infarct size was assessed by MRI after 24 hours reperfusion. Immune cell mobilization and infiltration was assessed by flow cytometry. We found that myeloid Mcl1 knockout mice had significantly reduced infarct size when compared to heterozygous and wild type control mice (MyMcl1+/+: 78.0 mm3; MyMcl1+/−: 83.4 mm3; MyMcl1−/−: 55.1 mm3). This was accompanied by a nearly complete absence of neutrophils in the ischemic hemisphere of myeloid Mcl1 knockout mice. Although myeloid Mcl1 knockout mice were protected from cerebral infarction, no significant differences in neurological deficit or the mRNA expression of inflammatory genes (TNFα, IL-1β, and MCP1) were detected. Inhibition of neutrophil chemotaxis using CXCR2 pepducin treatment partially reduced neutrophil mobilization and recruitment to the brain after stroke, but did not reduce infarct size 24 hours after transient MCA occlusion. These data confirm that neutrophils have an important role in infarct development during stroke pathophysiology, and suggest that complete deficiency, but not partial inhibition, is necessary to prevent neutrophil-mediated injury during stroke.

LncRNA GAS5 Silencing Attenuates Oxygen-Glucose Deprivation/Reperfusion-Induced Injury in Brain Microvascular Endothelial Cells via miR-34b-3p-Dependent Regulation of EPHA4

“…We predicted the possible messenger RNA (mRNA) targets of miR-34b-3p using starBase database. EPHA4, 15 MCL1, 21 PDE4D, 22 BCL2L13, 23 GATA3 24 and ROCK1 25 were chosen due to their important regulatory functions in cerebral ischemia-reperfusion injury. EPHA4 was chosen for further analysis due to its the most significant negative regulatory relationship with miR-34b-3p ( Supplementary Figure 1B ).…”

The post-cardiac arrest syndrome: A case for lung–brain coupling and opportunities for neuroprotection

“…147 The lung as a site of neutrophil priming Because CA induces both systemic ischemia and inflammation, neutrophils are primed in the periphery long before reaching the CNS. 148 Yet, while genetic models of neutrophil deficiency support their role in exacerbating cerebral reperfusion injury, 149 anti-neutrophil strategies have failed in clinical trials for acute cerebral ischemia. 150 This apparent contradiction may reflect the fact that like microglia, neutrophils are also capable of adopting either pro-(N1) or anti-(N2) inflammatory phenotypes.…”

Aging exacerbates neutrophil pathogenicity in ischemic stroke

“…This is likely due, in large part, to the fact that many of the targeted molecules are not neutrophil-specific, leading to a high degree of nonspecificity. Interestingly, a recent study found that specific genetic deletion of neutrophils (Mcl1 knockout) did not improve neurological deficits after ischemic stroke in mice [25]. However, it is critically important to note that the Mcl1 study, and all previous anti-neutrophil therapies in acute ischemic stroke, were performed only in young animals.…”