Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice.
Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice.
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DOI：
10.4049/jimmunol.1100500
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Poynter ME
中科院分区：
文献类型：
--
作者：
Ather JL;Ckless K;Martin R;Foley KL;Suratt BT;Boyson JE;Fitzgerald KA;Flavell RA;Eisenbarth SC;Poynter ME
白介素1β是一些炎症性疾病的关键细胞因子，与致病性Th17反应有关。微生物和环境刺激激活NLRP3炎症体可以使caspase-1依赖的处理和分泌IL-1β。急性时相蛋白血清淀粉样蛋白A(SAA)在炎症反应中高度诱导，参与系统调节先天免疫和获得性免疫反应。严重过敏性哮喘患者存在IL-1β、SA和IL-17水平升高，但这些介质之间的机制关系尚未确定。在这里，我们证明了Saa3在暴露于几种混合Th2/Th17极化变态反应致敏方案的小鼠的肺中表达。肺内滴注SAA可引起依赖TLR2、MyD88和IL-1的肺中性粒细胞炎症。此外，SAA可促进IL-1α、IL-1β、IL-6、IL-23和前列腺素E_2的产生，促进树突状细胞成熟，并需要TLR2、MYD88和NLRP3炎性小体才能使树突状细胞和巨噬细胞分泌IL-1β。在SAA暴露的树突状细胞的条件培养液中多克隆刺激的CD4+T细胞产生IL-17，多克隆刺激的脾细胞分泌IL-17的能力依赖于IL-1、TLR2和NLRP3炎症体。此外，在过敏性呼吸道炎症模型中，肺内给予SAA作为佐剂，使小鼠对吸入的卵清蛋白敏感，导致抗原攻击后白细胞涌入，并依赖于IL-1受体信号，重新刺激脾细胞产生IL-17。
Interleukin (IL)-1β is a cytokine critical to several inflammatory diseases in which pathogenic TH17 responses are implicated. Activation of the NLRP3 inflammasome by microbial and environmental stimuli can enable the caspase-1 dependent processing and secretion of IL-1β. The acute phase protein serum amyloid A (SAA) is highly induced during inflammatory responses, wherein it participates in systemic modulation of innate and adaptive immune responses. Elevated levels of IL-1β, SAA, and IL-17 are present in subjects with severe allergic asthma, yet the mechanistic relationship between these mediators has yet to be identified. Herein, we demonstrate that Saa3 is expressed in the lung of mice exposed to several mixed Th2/Th17-polarizing allergic sensitization regimens. SAA instillation into the lungs elicits robust TLR2-, MyD88-, and IL-1-dependent pulmonary neutrophilic inflammation. Furthermore, SAA drives production of IL-1α, IL-1β, IL-6, IL-23, and PGE2, causes dendritic cell maturation, and requires TLR2, MyD88, and the NLRP3 inflammasome for secretion of IL-1β by dendritic cells and macrophages. CD4+ T cells polyclonally stimulated in the presence of conditioned media from SAA-exposed dendritic cells produced IL-17 and the capacity of polyclonally-stimulated splenocytes to secrete IL-17 is dependent upon IL-1, TLR2, and the NLRP3 inflammasome. Additionally, in a model of allergic airway inflammation, administration of SAA to the lungs functions as an adjuvant to sensitize mice to inhaled ovalbumin, resulting in leukocyte influx after antigen challenge and a predominance of IL-17 production from restimulated splenocytes that is dependent upon IL-1 receptor signaling.
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影响因子：
4.3
作者：
Barczyk, A;Pierzchala, W;Sozañska, E
通讯作者：
Sozañska, E
影响因子：
20.3
作者：
Chizzolini, Carlo;Chicheportiche, Rachel;Dayer, Jean-Michel
通讯作者：
Dayer, Jean-Michel
血清淀粉样蛋白 A 通过独立于甲酰肽受体-1 的受体介导人中性粒细胞产生活性氧
影响因子：
5.5
作者：
Bjoerkman, Lena;Karlsson, Jennie;Dahlgren, Claes
通讯作者：
Dahlgren, Claes
影响因子：
2.2
作者：
Büyüköztürk, S;Gelincik, AA;Çolakoglu, B
通讯作者：
Çolakoglu, B
影响因子：
4.4
作者：
He, Rong;Shepard, Larry W.;Ye, Richard D.
通讯作者：
Ye, Richard D.