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.
Objective: The intersection between immunology and metabolism contributes to the pathogenesis of obesity-associated metabolic diseases as well as molecular control of inflammatory responses. The metabolite itaconate and the cell-permeable derivatives have robust anti-inflammatory effects; therefore, it is hypothesized that cis-aconitate decarboxylase (Acod1)-produced itaconate has a protective, anti-inflammatory effect during diet-induced obesity and metabolic disease.Methods: Wild-type and Acod1 À/À mice were subjected to diet-induced obesity.Glucose metabolism was analyzed by glucose tolerance tests, insulin tolerance tests, and indirect calorimetry. Gene expression and transcriptome analysis was performed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and RNA sequencing.Results: Wild-type and Acod1 À/À mice on high-fat diet had equivalent weight gain, but Acod1 À/À mice had impaired glucose metabolism. Insulin tolerance tests and glucose tolerance tests after 12 weeks on high-fat diet revealed significantly higher blood glucose levels in Acod1 À/À mice. This was associated with significant enrichment of inflammatory gene sets and a reduction in genes related to adipogenesis and fatty acid metabolism. Analysis of naive Acod1 À/À mice showed a significant increase in fat deposition at 3 and 6 months of age and obesity and insulin resistance by 12 months. Conclusions:The data show that Acod1 has an important role in the regulation of glucose homeostasis and obesity under normal and high-fat diet conditions.
Objective Excess dietary fat and sodium (NaCl) are both associated with obesity and metabolic dysfunction. In mice, high NaCl has been shown to block high‐fat (HF) diet–induced weight gain. Here, the impact of an HF/NaCl diet on metabolic function in the absence of obesity was investigated. Methods Wild‐type mice were administered chow, NaCl (4%), HF, and HF/NaCl diets. Metabolic analysis was performed by measuring fasted blood glucose and insulin levels and by glucose tolerance test and insulin tolerance test. Results After 10 weeks on diets, male and female mice on the HF diet gained weight, and HF/NaCl mice had significantly reduced weight gain similar to chow‐fed mice. In the absence of obesity, HF/NaCl mice had significantly elevated fasting blood glucose and impaired glucose control during glucose tolerance tests. Both NaCl and HF/NaCl mice had decreased pancreas and β‐cell mass. Administration of NaCl in drinking water did not protect mice from HF‐diet‐induced weight gain and obesity. Further analysis revealed that longer administration of HF/NaCl diets for 20 weeks resulted in significant weight gain and insulin resistance. Conclusions The data demonstrate that despite early inhibitory effects on fat deposition and weight gain, an HF/NaCl diet does not prevent the metabolic consequences of HF diet consumption.
IL4Rα signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4Rα signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4Rα signaling in cardiac remodeling post-MI. We established a murine myeloid-specific IL4Rα knockout (MyIL4RαKO) murine model with LysM promoter-driven Cre recombination. Macrophages from MyIL4RαKO mice showed significant down-regulation of alternatively activated macrophage markers but an up-regulation of classical activated macrophage markers both in vitro and in vivo, indicating the successful inactivation of IL4Rα signaling in macrophages. To examine the role of myeloid IL4Rα during MI, we subjected MyIL4RαKO and littermate floxed control (FC) mice to MI. We found that cardiac function was significantly impaired as a result of myeloid-specific IL4Rα deficiency. This deficiency resulted in a dysregulated inflammatory response consisting of decreased production of anti-inflammatory cytokines. Myeloid IL4Rα deficiency also led to reduced collagen 1 deposition and an imbalance of MMPs/TIMPs, with upregulated matrix metalloproteinases (MMPs) and downregulated tissue inhibitors of metalloproteinases (TIMPs), which resulted in insufficient fibrotic remodeling. In conclusion, this study identifies that myeloid-specific IL4Rα signaling regulates inflammation and fibrotic remodeling during MI. Therefore, myeloid-specific activation of IL4Rα signaling could offer protective benefits after MI.
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