Inflammatory Role of ASC in Antigen-Induced Arthritis Is Independent of Caspase-1, NALP-3, and IPAF
Inflammatory Role of ASC in Antigen-Induced Arthritis Is Independent of Caspase-1, NALP-3, and IPAF
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DOI：
10.4049/jimmunol.0802173
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发表时间：
2009-09-15
影响因子：
4.4
通讯作者：
Busso, Nathalie
中科院分区：
文献类型：
--
作者：
Kolly, Laeticia;Karababa, Mahir;Busso, Nathalie
由于IL-1β在人和小鼠关节炎的炎症中起重要作用，我们研究了炎症体成分ASC、NALP-3、IPAF和caspase-1的作用。到炎症性关节炎。我们首先研究了Asc缺陷和野生型小鼠在Ag诱导的关节炎(AIA)过程中的表型。ASC(-/-)小鼠表现出AIA的严重程度减轻，滑膜IL-1β水平降低，血清淀粉样蛋白A水平降低。相反，缺乏NALP-3、IPAF或caspase-1的小鼠没有表现出任何关节炎症的改变，因此表明ASC对AIA的相关作用不依赖于经典的NALP-3或IPAF炎症体。由于ASC是一种普遍存在的细胞质蛋白，参与了多种细胞过程，我们探索了ASC可能调节炎症的其他途径。在体外，ASC缺陷小鼠的淋巴和脾细胞的Ag特异性增殖显著降低，产生的干扰素-γ显著降低，而IL-10的产生增加。在抗CD28抗体存在或不存在的情况下，用抗CD3抗体连接TCR可诱导ASC(-/-)T细胞与野生型T细胞相比增殖能力降低。在体内，ASC(-/-)小鼠的淋巴结细胞增殖也显著降低，但在体外和体内都没有观察到对细胞凋亡的影响。综上所述，这些结果有力地表明，ASC通过其对细胞介导的免疫反应的影响而不是通过其在炎症小体形成中的作用来调节AIA的关节炎症。免疫学杂志，2009,183：4003-4012。
Because IL-1 beta plays an important role in inflammation in human and murine arthritis, we investigated the contribution of the inflammasome components ASC, NALP-3, IPAF, and caspase-1. to inflammatory arthritis. We first studied the phenotype of ASC-deficient and wild-type mice during Ag-induced arthritis (AIA). ASC(-/-) mice showed reduced severity of AIA, decreased levels of synovial IL-1 beta, and diminished serum amyloid A levels. In contrast, mice deficient in NALP-3, IPAF, or caspase-1 did not show any alteration of joint inflammation, thus indicating that ASC associated effects on AIA are independent of the classical NALP-3 or IPAF inflammasomes. Because ASC is a ubiquitous cytoplasmic protein that has been implicated in multiple cellular processes, we explored other pathways through which ASC may modulate inflammation. Ag-specific proliferation of lymph node and spleen cells from ASC-deficient mice was significantly decreased in vitro, as was the production of IFN-gamma, whereas IL-10 production was enhanced. TCR ligation by anti-CD3 Abs in the presence or absence of anti-CD28 Abs induced a reduction in T cell proliferation in ASC(-/-) T cells compared with wild-type ones. In vivo lymph node cell proliferation was also significantly decreased in ASC(-/-) mice, but no effects on apoptosis were observed either in vitro or in vivo in these mice. In conclusion, these results strongly suggest that ASC modulates joint inflammation in AIA through its effects on cell-mediated immune responses but not via its implication in inflammasome formation. The Journal of Immunology, 2009, 183: 4003-4012.