Rickettsia australis Activates Inflammasome in Human and Murine Macrophages.
Rickettsia australis Activates Inflammasome in Human and Murine Macrophages.
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澳大利亚人力体激活人和鼠巨噬细胞中的炎症体。
DOI：
10.1371/journal.pone.0157231
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fang R
中科院分区：
文献类型：
--
作者：
Smalley C;Bechelli J;Rockx-Brouwer D;Saito T;Azar SR;Ismail N;Walker DH;Fang R
立克次体主动地从空泡中逃逸，并在宿主细胞的细胞质中自由复制，在那里炎性体调查入侵的病原体。在本研究中，我们研究了在小鼠和人类巨噬细胞中的南方立克次体与炎性小体的相互作用。R. australis诱导人巨噬细胞显著水平的IL-1β分泌，与未处理的对照相比，用半胱天冬酶-1抑制剂处理后，IL-1β分泌显著降低，表明半胱天冬酶-1依赖性炎性体活化。立克次体感染小鼠骨髓源性巨噬细胞后8-12 h即能诱导巨噬细胞分泌IL-1β和IL-18。剂量依赖性这些细胞因子的分泌伴随着caspase-1的切割，并且在caspase-1/caspase-11缺陷的Bceptin或含有caspase激活和募集结构域（ASC）的与凋亡相关的斑点样蛋白中被完全消除，这表明R. australis激活ASC依赖性炎性小体。有趣的是，与野生型（WT）对照相比，响应于相同量的立克次体，NLRP 3-/-Bacteria显著降低IL-1β的分泌水平，表明NLRP 3炎性体有助于立克次体的胞质识别。澳洲试管苗立克次体在脾脏的载量，而在肝和肺的载量则不明显。与WT小鼠相比，澳大利亚人感染的NLRP 3-/-小鼠的感染率显著更高。这些数据表明，NLRP 3炎性体以组织特异性方式在体内宿主控制细菌中起作用。综上所述，我们的数据，第一次，阐明了ASC依赖的炎性小体的激活由R。australis在其中涉及NLRP 3的巨噬细胞中的表达。
Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8–12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. australis activate the ASC-dependent inflammasome. Interestingly, in response to the same quantity of rickettsiae, NLRP3-/- BMMs significantly reduced the secretion level of IL-1β compared to wild type (WT) controls, suggesting that NLRP3 inflammasome contributes to cytosolic recognition of R. australis in vitro. Rickettsial load in spleen, but not liver and lung, of R. australis-infected NLRP3-/- mice was significantly greater compared to WT mice. These data suggest that NLRP3 inflammasome plays a role in host control of bacteria in vivo in a tissue-specific manner. Taken together, our data, for the first time, illustrate the activation of ASC-dependent inflammasome by R. australis in macrophages in which NLRP3 is involved.