C5a and Bradykinin Receptor Cross-Talk Regulates Innate and Adaptive Immunity in Trypanosoma cruzi Infection
C5a and Bradykinin Receptor Cross-Talk Regulates Innate and Adaptive Immunity in Trypanosoma cruzi Infection
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DOI：
10.4049/jimmunol.1302417
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发表时间：
2014-10
期刊：
影响因子：
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通讯作者：
V. Schmitz;L. N. Almeida;Erik Svensjö;A. Monteiro;J. Köhl;J. Scharfstein
中科院分区：
文献类型：
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作者：
V. Schmitz;L. N. Almeida;Erik Svensjö;A. Monteiro;J. Köhl;J. Scharfstein
补体和激肽释放酶-激肽释放素级联系统在受损组织中都被激活。人们对它们在恰加斯病免疫病理机制中的合作关系知之甚少。恰加斯病是一种由细胞内原生动物克氏锥虫引起的慢性感染。在这项研究中，我们证明了C5a受体(C5aR)或缓激肽B2受体(B2R)的药理靶向可以抑制局部暴露于组织培养的锥虫(TCTS)的金黄地鼠颊囊内的血浆渗漏。此外，血管紧张素转换酶抑制剂通过激活C5aR/B2R或C3aR/B2R之间的联合通路，加强了TCT诱导的BALB/c、C57BL/6和C5缺陷A/J小鼠的脚掌肿胀。除了通过寄生虫来源的克鲁兹痛产生C5a和激动素外，我们还证明巨噬细胞通过联合激活C5aR/B2R更有效地内化TCTS。此外，我们发现C5aR靶向显著减少了NO的产生和巨噬细胞内的寄生。然后，我们研究了TCT感染中C5aR/B2R串扰对获得性免疫发展的影响。我们发现，通过阻断C5aR或B2R，IL-12p40/70在脾树突状细胞中的表达被钝化，这表明通过C5aR和B2R的共显性信号刺激Th1极化细胞因子的产生。最后，我们评估了在携带寄生虫的组织中释放的激动素和C5a对Th细胞分化的影响。正如预测的那样，经血管紧张素转换酶抑制剂预处理的BALB/c小鼠通过C5aR/B2R串扰增强了抗原特异性T细胞产生干扰素-γ。有趣的是，我们发现B2R靶向上调IL-10的分泌，而C5aR阻断则强烈刺激IL-4的产生。总之，我们描述了一种新的途径，通过C5aR/B2R串扰将血浆蛋白的跨内皮泄漏耦合到协调抗寄生虫免疫的细胞因子回路。
Complement and the kallikrein–kinin cascade system are both activated in injured tissues. Little is known about their partnership in the immunopathogenesis of Chagas disease, the chronic infection caused by the intracellular protozoan Trypanosoma cruzi. In this study, we show that pharmacological targeting of the C5a receptor (C5aR) or the bradykinin B2 receptor (B2R) inhibited plasma leakage in hamster cheek pouch topically exposed to tissue culture trypomastigotes (TCTs). Further, angiotensin-converting enzyme inhibitors potentiated TCT-evoked paw edema in BALB/c, C57BL/6, and C5-deficient A/J mice through activation of joint pathways between C5aR/B2R or C3aR/B2R. In addition to generation of C5a and kinins via parasite-derived cruzipain, we demonstrate that macrophages internalize TCTs more efficiently through joint activation of C5aR/B2R. Furthermore, we found that C5aR targeting markedly reduces NO production and intracellular parasitism in macrophages. We then studied the impact of C5aR/B2R cross-talk in TCT infection on the development of adaptive immunity. We found that IL-12p40/70 expression was blunted in splenic dendritic cells by blocking either C5aR or B2R, suggesting that codominant signaling via C5aR and B2R fuels production of the Th1-polarizing cytokine. Finally, we assessed the impact of kinins and C5a liberated in parasite-laden tissues on Th cell differentiation. As predicted, BALB/c mice pretreated with angiotensin-converting enzyme inhibitors potentiated IFN-γ production by Ag-specific T cells via C5aR/B2R cross-talk. Interestingly, we found that B2R targeting upregulated IL-10 secretion, whereas C5aR blockade vigorously stimulated IL-4 production. In summary, we describe a novel pathway by which C5aR/B2R cross-talk couples transendothelial leakage of plasma proteins to the cytokine circuitry that coordinates antiparasite immunity.