Kitamura Akiko, Sasaki Yuki, Abe Takaya, Kano Hirotsugu, Yasutomo Koji
Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima 770-8503, Japan.
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Chuou-ku, Kobe 650-0047, Japan.
J Exp Med. 2014 Nov 17;211(12):2385-96. doi: 10.1084/jem.20141091. Epub 2014 Nov 10.
Autoinflammatory syndromes cause sterile inflammation in the absence of any signs of autoimmune responses. Familial cold autoinflammatory syndrome (FCAS) is characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold stimuli. We have identified a missense mutation in the NLRC4 gene in patients with FCAS. NLRC4 has been known as a crucial sensor for several Gram-negative intracellular bacteria. The mutation in NLRC4 in FCAS patients promoted the formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase production of IL-1β. Transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis. Inflammation within tissues depended on IL-1β-mediated production of IL-17A from neutrophils but not from T cells. Our findings reveal a previously unrecognized link between NLRC4 and a hereditary autoinflammatory disease and highlight the importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases.
自身炎症性综合征在没有任何自身免疫反应迹象的情况下引发无菌性炎症。家族性冷自身炎症综合征（FCAS）的特征是在接触冷刺激后出现间歇性皮疹、关节痛和发热。我们在FCAS患者中鉴定出NLRC4基因的一个错义突变。NLRC4已知是几种革兰氏阴性胞内细菌的关键传感器。FCAS患者中NLRC4的突变促进了含NLRC4的炎性小体的形成，该炎性小体可切割前半胱天冬酶-1并增加IL-1β的产生。在恒定链启动子控制下表达突变型Nlrc4的转基因小鼠出现了皮炎和关节炎。组织内的炎症依赖于IL-1β介导的中性粒细胞而非T细胞产生IL-17A。我们的研究结果揭示了NLRC4与一种遗传性自身炎症性疾病之间此前未被认识到的联系，并突出了NLRC4不仅在对细菌感染的固有免疫反应中而且在炎症性疾病发生中的重要性。
