IL-22 modulates IL-17A production and controls inflammation and tissue damage in experimental dengue infection
IL-22 modulates IL-17A production and controls inflammation and tissue damage in experimental dengue infection
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DOI：
10.1002/eji.201243229
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发表时间：
2013-06-01
影响因子：
5.4
通讯作者：
Teixeira, Mauro M.
中科院分区：
文献类型：
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作者：
Guabiraba, Rodrigo;Besnard, Anne-Gaelle;Teixeira, Mauro M.
登革病毒(DENV)是一种蚊媒黄病毒，在许多热带国家是一个公共卫生问题。IL-22和IL-17A是多种感染性和炎症性疾病的关键细胞因子。我们使用一种小鼠适应的DENV 2型病毒株(P23085)评估了IL-22和IL-17A在实验性登革热感染发病机制中的作用，这种病毒株导致的疾病类似于人类的严重登革热。我们发现在免疫能力强的小鼠中，DENV-2感染后产生IL-22和IL-17A。感染IL-22(-/-)的小鼠的致死率增加，中性粒细胞聚集，组织中的促炎细胞因子增加，尤其是IL-17A。感染IL-22(-/-)小鼠的脾和肝脏病毒载量增加。从转氨酶水平和组织病理学来看，也有更严重的肝脏损伤。在肝脏和脾中，γ-增量T细胞和NK细胞分别是IL-17A和IL-22的来源。我们还发现，用重组人IL-22处理DENV感染的HepG2细胞可以减少细胞死亡和减少IL-6的产生。IL-17RA(-/-)小鼠在感染时受到保护，IL-17A中和抗体治疗部分逆转了IL-22(-/-)感染小鼠的表型。我们认为，破坏IL-22和IL-17A水平之间的平衡可能是减少与严重登革热感染相关的炎症和组织损伤的重要策略。
Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. IL-22 and IL-17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL-22 and IL-17A in the pathogenesis of experimental dengue infection using a mouse-adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL-22 and IL-17A are produced upon DENV-2 infection in immune-competentmice. Infected IL-22(-/-) mice had increased lethality, neutrophil accumulation and pro-inflammatory cytokines in tissues, notably IL-17A. Viral load was increased in spleen and liver of infected IL-22(-/-) mice. There was also more severe liver injury, as seen by increased transaminases levels and tissue histopathology. gamma delta T cells and NK cells are sources of IL-17A and IL-22, respectively, in liver and spleen. We also show that DENV-infected HepG2 cells treated with rhIL-22 had reduced cell death and decreased IL-6 production. IL-17RA(-/-) mice were protected upon infection and IL-17A-neutralizing-Ab-treatment partially reversed the phenotype observed in IL-22(-/-)-infected mice. We suggest that disrupting the balance between IL-22 and IL-17A levels may represent an important strategy to reduce inflammation and tissue injury associated with severe dengue infection.