Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1
Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1
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DOI：
10.1016/j.immuni.2006.02.004
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发表时间：
2006-03-01
期刊：
影响因子：
32.4
通讯作者：
Flavell, RA
中科院分区：
文献类型：
--
作者：
Sutterwala, FS;Ogura, Y;Flavell, RA
NALP 3/CIAS 1/cryopyrin基因的突变与三种自身炎症性疾病有关：Muckle-Wells综合征，家族性寒冷自身炎症综合征和慢性婴儿神经皮肤和关节综合征。已经提出NALP 3与衔接分子ASC形成半胱天冬酶-1激活的“炎性体”，一种具有前IL 1 β加工活性的复合物。在这里，我们证明了NALP 3缺乏对caspase-1功能的影响。NALP 3对于脂多糖刺激的巨噬细胞中ATP驱动的caspase-1活化以及caspase-1依赖性细胞因子IL-1 α、IL-1 β和IL-18的有效分泌至关重要。IL-1 β已被证明在接触性超敏反应中发挥关键作用;我们发现ASC和NALP 3缺陷小鼠也表现出对半抗原三硝基苯基氯的接触性超敏反应受损。然而，NALP 3不是鼠伤寒沙门氏菌激活caspase-1所必需的，并且NALP 3缺陷仅部分保护小鼠免受内毒素的致死作用。这些数据表明，NALP 3在caspase-1活化途径中发挥特定作用。
Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1 beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1 alpha, IL-1 beta, and IL-18. IL-1 beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway.