Leishmania infantum Parasites Subvert the Host Inflammatory Response through the Adenosine A2(A) Receptor to Promote the Establishment of Infection.
Leishmania infantum Parasites Subvert the Host Inflammatory Response through the Adenosine A2(A) Receptor to Promote the Establishment of Infection.
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DOI：
10.3389/fimmu.2017.00815
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发表时间：
2017
影响因子：
7.3
通讯作者：
Carregaro V
中科院分区：
文献类型：
--
作者：
Lima MHF;Sacramento LA;Quirino GFS;Ferreira MD;Benevides L;Santana AKM;Cunha FQ;Almeida RP;Silva JS;Carregaro V
腺苷是一种内源性释放的嘌呤核苷，通过四种广泛表达的G蛋白偶联受体：A1，A2 A，A2 B和A3发出信号。其中，A2 AR被认为介导主要的腺苷抗炎活性。在皮肤利什曼病期间，腺苷诱导免疫抑制，从而促进感染的建立。在此，我们证明了A2 AR信号被婴儿利什曼原虫寄生虫（导致内脏利什曼病的病原体）利用，以成功地定殖脊椎动物宿主。A2 AR基因缺失小鼠表现出良好的细胞反应，在寄生器官中具有强烈的Th 1免疫应答。在A2 AR −/−小鼠中观察到活化的中性粒细胞向疾病靶器官的强烈浸润。这些细胞的特征在于其细胞表面上CXCR 2和CD 69的高表达以及cxcl 1表达的增加。有趣的是，这种表型是由IFN-γ介导的，其基础是对这种细胞因子特异性的中和抗体阻止嗜中性粒细胞流入寄生器官。在评估免疫抑制作用时，我们发现在A2 AR −/−感染的小鼠中，CD 4 + FOXP 3 + T细胞数量减少，il 10表达减少。在离体细胞培养过程中，A2 AR −/−脾细胞产生的IL-10数量较少。总之，我们证明了A2 AR信号通路对Th 1型适应性免疫的发展是有害的，并且该通路可能与调节过程相关。特别是，它促进了寄生虫监测。
Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2A, A2B, and A3. Of these, A2AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A2AR signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. A2AR gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in A2AR−/− mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased cxcl1 expression. Interestingly, this phenotype was mediated by IFN-γ on the basis that a neutralizing antibody specific to this cytokine prevented neutrophilic influx into parasitized organs. In evaluating the immunosuppressive effects, we identified a decreased number of CD4+ FOXP3+ T cells and reduced il10 expression in A2AR−/− infected mice. During ex vivo cell culture, A2AR−/− splenocytes produced smaller amounts of IL-10. In conclusion, we demonstrated that the A2AR signaling pathway is detrimental to development of Th1-type adaptive immunity and that this pathway could be associated with the regulatory process. In particular, it promotes parasite surveillance.