A new mechanism regulating the initiation of allergic airway inflammation
A new mechanism regulating the initiation of allergic airway inflammation
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DOI：
10.1016/j.jaci.2007.04.025
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发表时间：
2007-08-01
影响因子：
14.2
通讯作者：
Corry, David B.
中科院分区：
文献类型：
--
作者：
Kiss, Attila;Montes, Martin;Corry, David B.
背景资料：过敏原诱导的最早期免疫事件知之甚少，但可能是了解过敏性炎症是如何建立的必要条件。目的：我们试图描述过敏原激活的最早期信号传导事件，并确定其对过敏性炎症的意义。将真菌相关变应原蛋白酶（FAP）或卵清蛋白鼻内给予野生型小鼠一次，以确定其诱导变态反应的能力。相关基因并引发过敏性肺部炎症。对重组酶激活基因1、C3 a、C3 a过敏毒素受体和MyD 88缺陷的小鼠进行类似的激发，以了解这些分子以及T和B细胞对过敏性炎症的需求。连续T细胞转移实验进一步进行，以确定是否信号转导和转录激活因子6（STAT 6）所需的细胞招聘和过敏性inflammation.Results：FAP，但不是卵白蛋白，诱导嗜酸性粒细胞的气道炎症和肺IL-4的生产在没有适应性免疫细胞的过敏特异性气道趋化因子的转录诱导后。变应原介导的趋化因子分泌和先天性过敏性肺炎发生在没有STAT 6，重组酶激活基因1，C3 a，C3 a过敏毒素受体，Toll样受体4，MyD 88，但需要完整的蛋白酶活性。此外，FAP诱导T（H）2细胞和嗜酸性粒细胞向肺的募集独立于STAT 6，而STAT 6以前被认为是T（H）2细胞归巢所必需的。结论：FAP通过以前未被认识的先天免疫信号传导机制诱导变应性肺炎。这些发现揭示了一个新的范式，了解如何过敏性炎症开始，并提出了新的可能性，为预防和治疗过敏性疾病，如哮喘。
Background: The earliest immune events induced by allergens are poorly understood, yet are likely essential to understanding how allergic inflammation is established.Objective: We sought to describe the earliest signaling events activated by allergen and determine their significance to allergic inflammation.Methods: A fungal-associated allergenic proteinase (FAP) or ovalbumin was administered once intranasally to wild-type mice to determine their ability to induce allergy-associated genes and initiate allergic lung inflammation. Mice deficient in recombinase activating gene 1, C3a, the C3a anaphylatoxin receptor, and MyD88 were challenged similarly to understand the requirement of these molecules and T and B cells for allergic inflammation. Adoptive T-cell transfer experiments were further performed to determine whether signal transducer and activator of transcription 6 (STAT6) was required for cell recruitment and allergic inflammation.Results: FAP, but not ovalbumin, induced eosinophilic airway inflammation and lung IL-4 production in the absence of adaptive immune cells after the transcriptional induction of allergy-specific airway chemokines. Allergen-mediated chemokine secretion and innate allergic lung inflammation occurred in the absence of STAT6, recombinase activating gene 1, C3a, C3a anaphylatoxin receptor, Toll-like receptor 4, and MyD88 but required intact proteinase activity. Furthermore, FAP induced recruitment of T(H)2 cells and eosinophils to lungs independently of STAT6, which was previously thought to be required for T(H)2 cell homing.Conclusion: FAP induces allergic lung inflammation through a previously unrecognized innate immune signaling mechanism.Clinical implications: These findings reveal a new paradigm for understanding how allergic inflammation begins and suggest novel possibilities for the prevention and treatment of allergic diseases, such as asthma.