Deregulation of inflammatory response in the diabetic condition is associated with increased ischemic brain injury

Abstract

BackgroundAlthough elicited inflammation contributes to tissue injury, a certain level of inflammation is necessary for subsequent tissue repair/remodeling. Diabetes, a chronic low-grade inflammatory state, is a predisposing risk factor for stroke. The condition is associated with delayed wound healing, presumably due to disrupted inflammatory responses. With inclusion of the diabetic condition in an experimental animal model of stroke, this study investigates whether the condition alters inflammatory response and influences stroke-induced brain injury.MethodsC57BL/6 mice were fed a diabetic diet (DD) for 8 weeks to induce an experimental diabetic condition or a normal diet (ND) for the same duration. Gene expression of inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), CCR2, and CD36 was assessed in the peripheral immune cells and brains of normal and diabetic mice before and after focal cerebral ischemia. The expression of these factors was also determined in lipopolysaccharide (LPS)-treated cultured normal and diabetic macrophages. Ischemic outcome was assessed in these mice at 3 days post-ischemia.ResultsDD intervention in mice resulted in obesity and elevated insulin and glucose level in the blood. The peritoneal immune cells from the diabetic mice showed higher MCP-1 mRNA levels before and after stroke. Compared to normal mice, diabetic mice showed reduced MCP-1, IL-6, and CCR2 gene expression in the brain at 6 h post-ischemia. LPS-stimulated inflammatory responses were also reduced in the diabetic macrophages. The diabetic mice showed larger infarct size and percent swelling.ConclusionsThese results showed that diabetic conditions deregulate acute inflammatory response and that the condition is associated with increased stroke-induced injury. The study suggests that interventions aimed at restoring appropriate inflammatory response in peripheral immune cells/macrophages may be beneficial in reducing stroke-induced brain injury in subjects with chronic inflammatory conditions.

Microglia and Monocyte-Derived Macrophages in Stroke

“…The exacerbation was associated with increased CD36 in the brain. In vitro LPS stimulation of peritoneal macrophages from diabetic mice attenuated the inflammatory response [187]. The blunted inflammatory response in diabetic macrophages was also reported in db/db mice, with decreased microglial activation and proinflammatory cytokines in the stroked brain [188].…”

“…Recently, we have reported the impact of diabetes on stroke outcomes. Diet-induced obese mice with insulin resistance and elevated fasting blood glucose levels had significant increases in infarct volume and edema [187]. The exacerbation was associated with increased CD36 in the brain.…”

“…These conditions are often associated with the exacerbation of ischemic outcomes and are predictive of worse recovery [186]. The inclusion of hyperlipidemia and diabetes in animal models of stroke has demonstrated that these conditions modulate postischemic inflammatory responses and lesion development [101,152,187,188]. In addition, increased inflammatory factors such as cytokines, chemokines, and adhesion molecules in peripheral monocytes/macrophages in these conditions suggest that peripheral immune status modulates CNS injury.…”

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke

“…Brains were excised, frozen, and sectioned using an unbiased stereological sampling strategy to reflect the MCA territory in both hemispheres as previously described (E. Kim et al, 2014). Tissue sections with 30 m thicknesses were collected serially at 600 m intervals for analysis of infarct volume and immunohistochemistry.…”

“…Although expressed less in the CNS, Abca1 promotes cholesterol efflux by preferentially lipidating naive ApoE, whereas Abcg1 acts on partially lipidated ApoE (Karten et al, 2006; W.S. Kim, et al, 2008). Notably, daidzein upregulates the expression of Abcg1 Gao et al, 2008), and it promotes axonal outgrowth in cultured hippocampal neurons via estrogen receptor signaling .…”