Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Front Immunol. 2022 Jun 16;13:864858. doi: 10.3389/fimmu.2022.864858. eCollection 2022.
Diabetic patients have larger infarcts, worse neurological deficits, and higher mortality rate after an ischemic stroke. Evidence shows that in diabetes, the hypothalamic-pituitary-adrenal (HPA) axis was dysregulated and levels of cortisol increased. Based on the role of the HPA axis in immunity, we hypothesized that diabetes-dysregulated stress response exacerbates stroke outcomes regulation of inflammation. To test this hypothesis, we assessed the regulation of the HPA axis in diabetic mice before and after stroke and determined its relevance in the regulation of post-stroke injury and inflammation. Diabetes was induced in C57BL/6 mice by feeding a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and then the mice were subjected to 30 min of middle cerebral artery occlusion (MCAO). Infarct volume and neurological scores were measured in the ischemic mice. The inflammatory cytokine and chemokine levels were also determined in the ischemic brain. To assess the effect of diabetes on the stroke-modulated HPA axis, we measured the expression of components in the HPA axis including corticotropin-releasing hormone (CRH) in the hypothalamus, proopiomelanocortin (POMC) in the pituitary, and plasma adrenocorticotropic hormone (ACTH) and corticosterone. Diabetic mice had larger infarcts and worse neurological scores after stroke. The exacerbated stroke outcomes in diabetic mice were accompanied by the upregulated expression of inflammatory factors (including IL-1β, TNF-α, IL-6, CCR2, and MCP-1) in the ischemic brain. We also confirmed increased levels of hypothalamic CRH, pituitary POMC, and plasma corticosterone in diabetic mice before and after stroke, suggesting the hyper-activated HPA axis in diabetic conditions. Finally, we confirmed that post-stroke treatment of metyrapone (an inhibitor of glucocorticoid synthesis) reduced IL-6 expression and the infarct size in the ischemic brain of diabetic mice. These results elucidate the mechanisms in which the HPA axis in diabetes exacerbates ischemic stroke. Maintaining an optimal level of the stress response by regulating the HPA axis may be an effective approach to improving stroke outcomes in patients with diabetes.
糖尿病患者在发生缺血性脑卒中后会出现更大的梗死灶、更严重的神经功能缺损和更高的死亡率。有证据表明，在糖尿病中，下丘脑-垂体-肾上腺（HPA）轴失调，皮质醇水平升高。基于 HPA 轴在免疫中的作用，我们假设糖尿病失调的应激反应会加剧脑卒中后的炎症反应。为了验证这一假设，我们评估了糖尿病小鼠在脑卒中前后 HPA 轴的调节情况，并确定了其在调节脑卒中后损伤和炎症中的相关性。通过给 C57BL/6 小鼠喂食高脂肪饮食和腹腔注射链脲佐菌素（STZ）来诱导糖尿病，然后使这些小鼠发生 30 分钟的大脑中动脉闭塞（MCAO）。在缺血性小鼠中测量梗死体积和神经学评分。还在缺血性大脑中测定了炎症细胞因子和趋化因子的水平。为了评估糖尿病对脑卒中调节的 HPA 轴的影响，我们测量了 HPA 轴的组成部分，包括下丘脑的促肾上腺皮质激素释放激素（CRH）、垂体的前阿黑皮素原（POMC）以及血浆中的促肾上腺皮质激素（ACTH）和皮质酮。糖尿病小鼠在发生脑卒中后梗死体积更大，神经学评分更差。在糖尿病小鼠中，脑卒中后炎症因子（包括 IL-1β、TNF-α、IL-6、CCR2 和 MCP-1）的表达上调，加剧了脑卒中的后果。我们还证实，在糖尿病小鼠发生脑卒中前后，下丘脑的 CRH、垂体的 POMC 和血浆中的皮质酮水平升高，表明糖尿病状态下 HPA 轴过度激活。最后，我们证实，脑卒中后给予米托坦（一种糖皮质激素合成抑制剂）可降低糖尿病小鼠缺血性大脑中的 IL-6 表达和梗死体积。这些结果阐明了糖尿病中 HPA 轴加剧缺血性脑卒中的机制。通过调节 HPA 轴来维持应激反应的最佳水平可能是改善糖尿病患者脑卒中预后的有效方法。
