STZ-induced diabetes exacerbates neurons ferroptosis after ischemic stroke by upregulating LCN2 in neutrophils
Huan Wang, Zhao Wang, Yuxiao Gao, Jingjing Wang, Yujia Yuan, Cong Zhang, Xiangjian Zhang
Abstract
Diabetic is a major contributor to the unfavorable prognosis of ischemic stroke. However, intensive hypoglycemic strategies do not improve stroke outcomes, implying that diabetes may affect stroke outcomes through other ways. Ferroptosis is a novel programmed cell death pathway associated with the development of diabetes and ischemic stroke. This study aimed to investigate the effect of streptozotocin (STZ)-induced diabetes on ferroptosis after stroke from the immune cell perspective, and to provide a theoretical foundation for the clinical management of ischemic stroke in patients with diabetes. The results revealed that STZ-induced diabetes not only facilitates the infiltration of neutrophils into the brain after stroke, but also upregulates the expression of lipocalin 2 (LCN2) in neutrophils. LCN2 promotes lipid peroxide accumulation by increasing intracellular ferrous ions, which intensify ferroptosis in major brain cell populations, especially neurons. Our findings suggest that STZ-induced diabetes aggravates ischemic stroke partially by mediating ferroptosis through neutrophil-derived LCN2. These data contribute to improved understanding of post-stroke immune regulation in diabetes, and offer a potentially novel therapeutic target for the management of acute-stage ischemic stroke complicated with diabetes. STZ-induced diabetes not only facilitates the infiltration of neutrophils into the brain after stroke, but also upregulates the expression of lipocalin 2 (LCN2) in neutrophils. LCN2 promotes lipid peroxide accumulation and dysregulation of REDOX response by increasing intracellular ferrous ions, which intensify ferroptosis in major brain cell populations, especially neurons. • STZ-induced diabetes upregulates the expression of LCN2 in neutrophils. • Neurons are more sensitive to ferroptosis induced by ischemic stroke compare to glial cell. • LCN2 increase intracellular Fe 2+ level and lipid peroxide in neurons after OGD.