Bradykinin B2 Receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses.
Bradykinin B2 Receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses.
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DOI：
10.1371/journal.ppat.0030185
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发表时间：
2007-11
期刊：
影响因子：
6.7
通讯作者：
Scharfstein J
中科院分区：
文献类型：
--
作者：
Monteiro AC;Schmitz V;Morrot A;de Arruda LB;Nagajyothi F;Granato A;Pesquero JB;Müller-Esterl W;Tanowitz HB;Scharfstein J
尽管树突状细胞（DCs）通过toll样受体识别病原体的概念被广泛接受，但我们最近提出，未成熟的树突状细胞可能通过触发g蛋白偶联的慢激肽B2受体（B2R）来感知克氏锥虫释放激肽的菌株。在此我们报告C57BL/6。与B2R+/+小鼠相比，腹腔感染克氏锥虫的B2R−/−小鼠表现出更高的寄生虫血症和死亡率。qRT-PCR结果显示，感染后14天克氏锥虫DNA增加了5倍。在B2R−/−心脏中])，而脾脏寄生在两种小鼠品系中都可以忽略不计。回忆反应分析（14 d p.i）显示，B2R−/−和野生型小鼠脾脏中产生IFN-γ的CD4+和CD8+ T细胞的频率很高且相当。然而，与野生型小鼠相比，从B2R−/−心脏分离的效应T细胞产生的IFN-γ显著减少。随着感染的持续，野生型小鼠的脾脏和心脏均出现IFN-γ-产生（CD4+CD44+和CD8+CD44+） T细胞，而B2R - / -小鼠的这种激活T细胞的频率可以忽略不计。此外，B2R - / -小鼠1型免疫应答的崩溃与抗原应答性CD4+ T细胞分泌IL-17和TNF-α的上调有关。组织培养trypmastigote与脾CD11c+ DC相互作用的体外分析表明，DC成熟（IL-12、CD40和CD86）受kinin/B2R通路控制。此外，全身注射trypomastigotes可诱导B2R+/+脾脏分离的CD11c+ dc产生IL-12，而B2R−/−小鼠的dc则不能。值得注意的是，将B2R+/+ CD11c+ dc过继转移（静脉注射）到B2R - / -小鼠体内，使它们能够抵抗急性攻击，恢复1型免疫的发育，并抑制TH17反应。总之，我们的研究结果表明，内源性成熟信号的DC传感器B2R的激活对于克氏锥虫感染获得性抗性的发展至关重要。抗体和产生IFN-γ的效应T细胞对于克氏锥虫感染的免疫控制至关重要，克氏锥虫是引起人类恰加斯病的细胞内原生动物。尽管抗寄生虫免疫的效力，寄生虫不能从它们的细胞内生态位清除。相反，低级别慢性感染盛行，引起心肌严重的免疫病理。虽然已经确定先天前哨细胞通过微生物结构受体（如toll样受体）感知克氏锥虫，但内源性炎症信号是否也有助于适应性免疫的发展仍不清楚。本研究的动机是意识到克氏锥虫（细胞外感染形式）配备了蛋白酶，可以从激肽原的内部片段释放促炎缓激肽。在这里，我们证明脾树突状细胞（dc），抗原呈递细胞，协调淋巴组织的适应性免疫分支，通过g蛋白偶联缓激肽B2受体（B2R）被有效激活。对b2r基因敲除小鼠感染结果的分析显示，由于产生IFN-γ效应T细胞的发育受损，突变小鼠产生了典型的易感表型。值得注意的是，b2r基因敲除小鼠的免疫功能障碍在野生型dc的细胞转移后得到纠正，从而将保护性T细胞的发育与dc对trypomastigotes释放的内源性危险信号（kinins）的感知联系起来。
Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B2 receptors (B2R). Here we report that C57BL/6.B2R−/− mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R+/+ mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B2R−/− heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-γ-producing CD4+ and CD8+ T cells in the spleen of B2R−/− and wild-type mice. However, production of IFN-γ by effector T cells isolated from B2R−/− heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-γ-producing (CD4+CD44+ and CD8+CD44+) T cells both in the spleen and heart while B2R−/− mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R−/− mice was linked to upregulated secretion of IL-17 and TNF-α by antigen-responsive CD4+ T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c+ DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c+ DCs isolated from B2R+/+ spleen, but not by DCs from B2R−/− mice. Notably, adoptive transfer of B2R+/+ CD11c+ DCs (intravenously) into B2R−/− mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed TH17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection. Antibodies and IFN-γ-producing effector T cells are essential for the immune control of infection by Trypanosoma cruzi, the intracellular protozoa that causes human Chagas disease. Despite the potency of anti-parasite immunity, the parasites are not cleared from their intracellular niches. Instead, a low grade chronic infection prevails, provoking severe immunopathology in the myocardium. Although it is well established that innate sentinel cells sense T. cruzi through receptors for microbial structures, such as Toll-like receptors, it remained unclear whether endogenous inflammatory signals also contribute to the development of adaptive immunity. The present study was motivated by awareness that T. cruzi trypomastigotes (extracellular infective forms) are equipped with proteases that liberate the pro-inflammatory bradykinin peptide from an internal segment of kininogens. Here we demonstrate that splenic dendritic cells (DCs), the antigen-presenting cells that coordinate the adaptive branch of immunity in lymphoid tissues, are potently activated via G-protein-coupled bradykinin B2 receptors (B2R). Analysis of the outcome of infection in B2R-knockout mice revealed that the mutant mice developed a typical susceptible phenotype, owing to impaired development of IFN-γ-producing effector T cells. Notably, the immune dysfunction of B2R-knockout mice was corrected upon cell transfer of wild-type DCs, thus linking development of protective T cells to DCs' sensing of endogenous danger signals (kinins) released by trypomastigotes.
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影响因子：
32.4
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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