Sheel Meru, Beattie Lynette, Frame Teija C M, de Labastida Rivera Fabian, Faleiro Rebecca J, Bunn Patrick T, Montes de Oca Marcela, Edwards Chelsea L, Ng Susanna S, Kumar Rajiv, Amante Fiona H, Best Shannon E, McColl Shaun R, Varelias Antiopi, Kuns Rachel D, MacDonald Kelli P A, Smyth Mark J, Haque Ashraful, Hill Geoff R, Engwerda Christian R
QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia;
QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia; School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia;
J Immunol. 2015 Dec 15;195(12):5707-17. doi: 10.4049/jimmunol.1501046. Epub 2015 Nov 4.
Intracellular infections, such as those caused by the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL), require a potent host proinflammatory response for control. IL-17 has emerged as an important proinflammatory cytokine required for limiting growth of both extracellular and intracellular pathogens. However, there are conflicting reports on the exact roles for IL-17 during parasitic infections and limited knowledge about cellular sources and the immune pathways it modulates. We examined the role of IL-17 in an experimental model of VL caused by infection of C57BL/6 mice with L. donovani and identified an early suppressive role for IL-17 in the liver that limited control of parasite growth. IL-17-producing γδ T cells recruited to the liver in the first week of infection were the critical source of IL-17 in this model, and CCR2(+) inflammatory monocytes were an important target for the suppressive effects of IL-17. Improved parasite control was independent of NO generation, but associated with maintenance of superoxide dismutase mRNA expression in the absence of IL-17 in the liver. Thus, we have identified a novel inhibitory function for IL-17 in parasitic infection, and our results demonstrate important interactions among γδ T cells, monocytes, and infected macrophages in the liver that can determine the outcome of parasitic infection.
细胞内感染，如由原生动物寄生虫杜氏利什曼原虫（内脏利什曼病的病原体）引起的感染，需要宿主强大的促炎反应来进行控制。白细胞介素-17（IL-17）已成为限制细胞外和细胞内病原体生长所需的一种重要促炎细胞因子。然而，关于IL-17在寄生虫感染期间的确切作用存在相互矛盾的报道，并且对其细胞来源及其调节的免疫途径了解有限。我们在C57BL/6小鼠感染杜氏利什曼原虫所致内脏利什曼病的实验模型中研究了IL-17的作用，并确定了IL-17在肝脏中的早期抑制作用，该作用限制了对寄生虫生长的控制。在感染第一周招募到肝脏中的产生IL-17的γδT细胞是该模型中IL-17的关键来源，并且CCR2(+)炎性单核细胞是IL-17抑制作用的重要靶点。改善的寄生虫控制与一氧化氮的产生无关，但与肝脏中在没有IL-17的情况下超氧化物歧化酶mRNA表达的维持有关。因此，我们确定了IL-17在寄生虫感染中的一种新抑制功能，并且我们的结果证明了肝脏中γδT细胞、单核细胞和被感染巨噬细胞之间的重要相互作用，这些相互作用可以决定寄生虫感染的结果。
