Department of Medicine, Division of Infectious Diseases.
Indiana University School of Medicine, Department of Microbiology & Immunology, Indiana University, Indianapolis, Indiana, USA.
JCI Insight. 2018 Sep 6;3(17). doi: 10.1172/jci.insight.120220.
Poorly controlled diabetes leads to comorbidities and enhanced susceptibility to infections. While the immune components involved in wound healing in diabetes have been studied, the components involved in susceptibility to skin infections remain unclear. Here, we examined the effects of the inflammatory lipid mediator leukotriene B4 (LTB4) signaling through its receptor B leukotriene receptor 1 (BLT1) in the progression of methicillin-resistant Staphylococcus aureus (MRSA) skin infection in 2 models of diabetes. Diabetic mice produced higher levels of LTB4 in the skin, which correlated with larger nonhealing lesion areas and increased bacterial loads compared with nondiabetic mice. High LTB4 levels were also associated with dysregulated cytokine and chemokine production, excessive neutrophil migration but impaired abscess formation, and uncontrolled collagen deposition. Both genetic deletion and topical pharmacological BLT1 antagonism restored inflammatory response and abscess formation, followed by a reduction in the bacterial load and lesion area in the diabetic mice. Macrophage depletion in diabetic mice limited LTB4 production and improved abscess architecture and skin host defense. These data demonstrate that exaggerated LTB4/BLT1 responses mediate a derailed inflammatory milieu that underlies poor host defense in diabetes. Prevention of LTB4 production/actions could provide a new therapeutic strategy to restore host defense in diabetes.
糖尿病控制不佳可导致合并症，并增加感染易感性。虽然已经研究了糖尿病伤口愈合中涉及的免疫成分，但与皮肤感染易感性相关的成分仍不清楚。在这里，我们研究了炎症脂质介质白三烯 B4（LTB4）通过其受体 B 白三烯受体 1（BLT1）在 2 型糖尿病模型中耐甲氧西林金黄色葡萄球菌（MRSA）皮肤感染进展中的作用。糖尿病小鼠皮肤产生的 LTB4 水平较高，与非糖尿病小鼠相比，其非愈合病变面积较大，细菌载量增加。高 LTB4 水平还与细胞因子和趋化因子产生失调、中性粒细胞过度迁移但脓肿形成受损以及胶原沉积失控有关。基因缺失和局部药理学 BLT1 拮抗均可恢复炎症反应和脓肿形成，随后降低糖尿病小鼠的细菌载量和病变面积。糖尿病小鼠中巨噬细胞耗竭可限制 LTB4 的产生并改善脓肿结构和皮肤宿主防御。这些数据表明，过度的 LTB4/BLT1 反应介导了一种脱轨的炎症微环境，这是糖尿病宿主防御能力下降的基础。预防 LTB4 的产生/作用可能为恢复糖尿病宿主防御提供一种新的治疗策略。
