ABSTRACT

Poorly controlled diabetes mellitus leads to several comorbidities, including susceptibility to infections. Hyperglycemia increases phagocyte responsiveness, however immune cells from people with diabetes show inadequate antimicrobial functions. We and others have shown that aberrant production of leukotriene B₄ (LTB₄) is detrimental to host defense in models of bacterial infection. Here, we will unveil the consequences of high glucose in the outcome of Leishmania braziliensis skin infection in people with diabetes and determine the role of LTB₄ in human phagocytes. We show that diabetes leads to higher systemic levels of LTB₄, IL-6 and TNF-α in cutaneous leishmaniasis. Only LTB₄ correlated with blood glucose levels and healing time in diabetes comorbidity. Skin lesions of people with leishmaniasis and diabetes exhibit increased neutrophil and amastigote numbers. Monocyte-derived macrophages from these individuals showed higher L. braziliensis loads, reduced production of Reactive Oxygen Species and unbalanced LTB₄/PGE₂ ratio. Our data reveal a systemic inflammation driven by diabetes comorbidity in opposition to a local reduced capacity to resolve L. braziliensis infection and a worse disease outcome.

摘要

糖尿病控制不佳会导致多种合并症，包括易受感染。高血糖会增加吞噬细胞的反应性，但糖尿病患者的免疫细胞显示出不足的抗菌功能。我们和其他人已经证明，白三烯 B ₄ (LTB ₄ ) 的异常产生不利于细菌感染模型中的宿主防御。在这里，我们将揭示高血糖对糖尿病患者巴西利什曼原虫皮肤感染的影响，并确定 LTB ₄在人类吞噬细胞中的作用。我们发现，糖尿病会导致皮肤利什曼病中LTB _{4 、IL-6 和 TNF-α 的全身水平升高。}只有 LTB ₄与糖尿病合并症的血糖水平和愈合时间相关。利什曼病和糖尿病患者的皮肤病变表现出中性粒细胞和无鞭毛体数量增加。来自这些个体的单核细胞来源的巨噬细胞表现出较高的巴西乳杆菌负荷、活性氧产生减少以及LTB ₄ /PGE ₂比率不平衡。我们的数据揭示了由糖尿病合并症驱动的全身炎症，与局部解决巴西乳杆菌感染的能力下降和更糟糕的疾病结果相反。