Involvement of Absent in Melanoma 2 in Inflammasome Activation in Macrophages Infected with Listeria monocytogenes
Involvement of Absent in Melanoma 2 in Inflammasome Activation in Macrophages Infected with Listeria monocytogenes
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DOI：
10.4049/jimmunol.1001058
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
K. Tsuchiya;H. Hara;I. Kawamura;T. Nomura;Takeshi Yamamoto;S. Daim;Sita R. Dewamitta;Yanna Shen;Rendong Fang;M. Mitsuyama
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作者：
K. Tsuchiya;H. Hara;I. Kawamura;T. Nomura;Takeshi Yamamoto;S. Daim;Sita R. Dewamitta;Yanna Shen;Rendong Fang;M. Mitsuyama
单核细胞增生李斯特菌侵入巨噬细胞的细胞质并诱导半胱天冬酶-1的活化以及随后的IL-1β和IL-18的成熟。尽管已证明含有半胱天冬酶激活和募集结构域（ASC）的凋亡相关斑点样蛋白（speck-like protein）在诱导对L.单核细胞增多症，其机制尚未完全阐明。在这项研究中，我们证明了黑色素瘤中的缺失2（AIM 2），一个最近被描述的细胞溶质DNA受体，在感染L。单核细胞增多症。Nod-like receptor family，pyrin domain containing 3（NLRP 3）和Nod-like receptor family，caspase activating and recruitment domain containing 4（NLRC 4）敲除的巨噬细胞对L.与从野生型巨噬细胞分泌的水平相比，单核细胞增多症的分泌仅略微降低，而ASC敲除巨噬细胞的分泌完全受损，表明NLRP 3和NLRC 4以外的受体也以ASC依赖性方式参与炎性小体活化。为了鉴定这些受体，研究了几种受体候选物（NLRP 2、NLRP 6、NLRP 12和AIM 2）诱导IL-1β分泌以响应L.使用在HEK 293细胞中重建的炎性小体系统比较单核细胞增多症。在这些受体候选者中，AIM 2赋予HEK 293细胞对细菌的最高反应性。AIM 2基因的敲除显著降低了L.单核细胞增多症感染的巨噬细胞。这些结果表明，AIM 2与NLRP 3和NLRC 4协同作用，在L.单核细胞增多症
Listeria monocytogenes invades the cytoplasm of macrophages and induces the activation of caspase-1 and the subsequent maturation of IL-1β and IL-18. Although apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC), an adaptor protein of nucleotide-binding oligomerization domain (Nod)-like receptors, has been shown to play an essential role in inducing this cellular response to L. monocytogenes, the mechanism has not been fully elucidated. In this study, we demonstrate the role of absent in melanoma 2 (AIM2), a recently described receptor of cytosolic DNA, in the activation of caspase-1 upon infection with L. monocytogenes. Secretion of IL-1β and IL-18 from Nod-like receptor family, pyrin domain containing 3 (NLRP3) and Nod-like receptor family, caspase-activating and recruitment domain containing 4 (NLRC4) knockout macrophages in response to L. monocytogenes was only slightly decreased compared with the levels secreted from wild-type macrophages, whereas secretion from ASC knockout macrophages was completely impaired, suggesting that receptors other than NLRP3 and NLRC4 also take part in inflammasome activation in an ASC-dependent manner. To identify such receptors, the abilities of several receptor candidates (NLRP2, NLRP6, NLRP12, and AIM2) to induce the secretion of IL-1β in response to L. monocytogenes were compared using the inflammasome system reconstructed in HEK293 cells. Among these receptor candidates, AIM2 conferred the highest responsiveness to the bacterium on HEK293 cells. Knockdown of AIM2 significantly decreased the secretion of IL-1β and IL-18 from L. monocytogenes-infected macrophages. These results suggest that AIM2, in cooperation with NLRP3 and NLRC4, plays an important role in the activation of caspase-1 during L. monocytogenes infection.