Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis
Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis
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DOI：
10.1073/pnas.1003738107
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发表时间：
2010-05-25
影响因子：
11.1
通讯作者：
Monack, Denise M.
中科院分区：
文献类型：
--
作者：
Jones, Jonathan W.;Kayagaki, Nobuhiko;Monack, Denise M.
巨噬细胞通过激活称为炎性小体的复合物内的半胱氨酸蛋白酶半胱天冬酶-1对胞质核酸作出反应。随后促炎细胞因子IL-1 β和IL-18的裂解和分泌对于先天免疫是至关重要的。在这里，我们表明，缺乏黑色素瘤2（AIM 2）的小鼠巨噬细胞不能感知胞质双链DNA，也不能触发炎性小体组装。响应于细胞内病原体土拉弗朗西斯菌的胱天蛋白酶-1活化也需要AIM 2。免疫荧光显微镜观察感染F.土拉热病揭示了细菌DNA与内源性AIM 2和炎性小体衔接子ASC的显著共定位。相比之下，I型IFN（IFN-α和IFN-β）分泌响应F。土拉热不需要AIM 2。然而，IFN-I确实通过增加AIM 2蛋白水平来促进AIM 2依赖性caspase- 1活化。因此，在缺乏IFN-I受体或干扰素基因刺激物（STING）的感染的巨噬细胞中，炎性小体活化减少。最后，AIM 2缺陷小鼠显示出对F.与野生型小鼠相比，土拉菌感染。他们体内增加的细菌负荷证实了AIM 2对有效的先天免疫应答至关重要。
Macrophages respond to cytosolic nucleic acids by activating cysteine protease caspase-1 within a complex called the inflammasome. Subsequent cleavage and secretion of proinflammatory cytokines IL-1 beta and IL-18 are critical for innate immunity. Here, we show that macrophages from mice lacking absent in melanoma 2 (AIM2) cannot sense cytosolic double-stranded DNA and fail to trigger inflammasome assembly. Caspase-1 activation in response to intracellular pathogen Francisella tularensis also required AIM2. Immunofluorescence microscopy of macrophages infected with F. tularensis revealed striking colocalization of bacterial DNA with endogenous AIM2 and inflammasome adaptor ASC. By contrast, type I IFN (IFN-alpha and -beta) secretion in response to F. tularensis did not require AIM2. IFN-I did, however, boost AIM2-dependent caspase- 1 activation by increasing AIM2 protein levels. Thus, inflammasome activation was reduced in infected macrophages lacking either the IFN-I receptor or stimulator of interferon genes (STING). Finally, AIM2-deficient mice displayed increased susceptibility to F. tularensis infection compared with wild-type mice. Their increased bacterial burden in vivo confirmed that AIM2 is essential for an effective innate immune response.