Almeida Débora de Fátima, Fraga-Silva Thais F de Campos, Santos Amanda R, Finato Angela C, Marchetti Camila M, Golim Marjorie de Assis, Lara Vanessa S, Arruda Maria S P, Venturini James
Laboratory of Experimental Immunopathology, Department of Chemistry, Universidade Estadual Paulista Bauru, Brazil.
Laboratory of Experimental Immunopathology, Department of Chemistry, Universidade Estadual PaulistaBauru, Brazil; Department of Microbiology and Immunology, Institute of Biosciences of Botucatu, Universidade Estadual PaulistaBotucatu, Brazil.
Front Cell Infect Microbiol. 2017 Jan 20;7:8. doi: 10.3389/fcimb.2017.00008. eCollection 2017.
Dermatophytosis is one of the most common human infections affecting both immunocompetent individuals and immunocompromised patients, in whom the disease is more aggressive and can reach deep tissues. Over the last decades, cases of deep dermatophytosis have increased and the dermatophyte-host interplay remains poorly investigated. Pattern recognition molecules, such as Toll-like receptors (TLR), play a crucial role against infectious diseases. However, there has been very little research reported on dermatophytosis. In the present study, we investigated the role of TLR2 during the development of experimental deep dermatophytosis in normal mice and mice with alloxan-induced diabetes mellitus, an experimental model of diabetes that exhibits a delay in the clearance of the dermatophyte, (Tm). Our results demonstrated that inoculation of Tm into the footpads of normal mice increases the expression of TLR2 in CD115Ly6C blood monocytes and, in hypoinsulinemic-hyperglycemic (HH) mice infected with Tm, the increased expression of TLR2 was exacerbated. To understand the role of TLR2 during the development of murine experimental deep dermatophytosis, we employed TLR2 knockout mice. Tm-infected TLR2 and TLR2 wild-type mice exhibited similar control of deep dermatophytic infection and macrophage activity; however, TLR2 mice showed a noteworthy increase in production of IFN-γ, IL-10, and IL-17, and an increased percentage of splenic CD25Foxp3 Treg cells. Interestingly, TLR2 HH-Tm mice exhibited a lower fungal load and superior organization of tissue inflammatory responses, with high levels of production of hydrogen peroxide by macrophages, alongside low TNF-α and IL-10; high production of IL-10 by spleen cells; and increased expansion of Tregs. In conclusion, we demonstrate that TLR2 diminishes the development of adaptive immune responses during experimental deep dermatophytosis and, in a diabetic scenario, acts to intensify a non-protective inflammatory response.
皮肤癣菌病是最常见的人类感染之一，影响免疫功能正常的个体和免疫功能低下的患者，在后者中疾病更具侵袭性且可累及深部组织。在过去几十年中，深部皮肤癣菌病的病例有所增加，而皮肤癣菌与宿主之间的相互作用仍研究不足。模式识别分子，如Toll样受体（TLR），在对抗传染病中起关键作用。然而，关于皮肤癣菌病的研究报道很少。在本研究中，我们调查了TLR2在正常小鼠和用四氧嘧啶诱导的糖尿病小鼠（一种表现出皮肤癣菌清除延迟的糖尿病实验模型）实验性深部皮肤癣菌病发展过程中的作用。我们的结果表明，将皮肤癣菌接种到正常小鼠的足垫中会增加CD115Ly6C血液单核细胞中TLR2的表达，而在感染皮肤癣菌的低胰岛素血症-高血糖（HH）小鼠中，TLR2表达的增加更为明显。为了了解TLR2在小鼠实验性深部皮肤癣菌病发展过程中的作用，我们使用了TLR2基因敲除小鼠。感染皮肤癣菌的TLR2基因敲除小鼠和TLR2野生型小鼠对深部皮肤癣菌感染和巨噬细胞活性表现出相似的控制；然而，TLR2基因敲除小鼠在IFN-γ、IL-10和IL-17的产生上有显著增加，并且脾脏CD25Foxp3调节性T细胞的百分比增加。有趣的是，TLR2 HH-皮肤癣菌小鼠表现出较低的真菌负荷和更好的组织炎症反应组织化，巨噬细胞产生高水平的过氧化氢，同时TNF-α和IL-10水平较低；脾细胞产生高水平的IL-10；以及调节性T细胞的扩增增加。总之，我们证明TLR2在实验性深部皮肤癣菌病期间会减少适应性免疫反应的发展，并且在糖尿病情况下，会加剧非保护性炎症反应。
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