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首页> 外文期刊>MBio >Complement Component 3C3 and C3a Receptor Are Required in Chitin-Dependent Allergic Sensitization to Aspergillus fumigatus but Dispensable in Chitin-Induced Innate Allergic Inflammation
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Complement Component 3C3 and C3a Receptor Are Required in Chitin-Dependent Allergic Sensitization to Aspergillus fumigatus but Dispensable in Chitin-Induced Innate Allergic Inflammation

机译：补充成分3C3和C3a受体在对烟曲霉的几丁质依赖性过敏致敏中是必需的，但在几丁质诱导的先天性过敏性炎症中是必需的

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Levels of the anaphylatoxin C3a are increased in patients with asthma compared with those in nonasthmatics and increase further still during asthma exacerbations. However, the role of C3a during sensitization to allergen is poorly understood. Sensitization to fungal allergens, such as Aspergillus fumigatus, is a strong risk factor for the development of asthma. Exposure to chitin, a structural polysaccharide of the fungal cell wall, induces innate allergic inflammation and may promote sensitization to fungal allergens. Here, we found that coincubation of chitin with serum or intratracheal administration of chitin in mice resulted in the generation of C3a. We established a model of chitin-dependent sensitization to soluble Aspergillus antigens to test the contribution of complement to these events. C3?/? and C3aR?/? mice were protected from chitin-dependent sensitization to Aspergillus and had reduced lung eosinophilia and type 2 cytokines and serum IgE. In contrast, complement-deficient mice were not protected against chitin-induced innate allergic inflammation. In sensitized mice, plasmacytoid dendritic cells from complement-deficient animals acquired a tolerogenic profile associated with enhanced regulatory T cell responses and suppressed Th2 and Th17 responses specific for Aspergillus. Thus, chitin induces the generation of C3a in the lung, and chitin-dependent allergic sensitization to Aspergillus requires C3aR signaling, which suppresses regulatory dendritic cells and T cells and induces allergy-promoting T cells. >IMPORTANCE Asthma is one of the fastest growing chronic illnesses worldwide. Chitin, a ubiquitous polymer in our environment and a key component in the cell wall of fungal spores and the exoskeletons of insects, parasites, and crustaceans, triggers innate allergic inflammation. However, there is little understanding of how chitin is initially recognized by mammals and how early recognition of chitin affects sensitization to environmental allergens and development of allergic asthma. The complement system is evolutionarily one of the oldest facets of the early or innate warning systems in mammals. We studied whether and how complement components influence the recognition of chitin and shape the downstream sensitization toward fungal allergens. We show here that complement recognition of chitin plays a critical role in shaping the behavior of dendritic cells, which in turn regulate the function of T cells that mediate allergic responses to fungi.
机译：与非哮喘患者相比，哮喘患者的过敏毒素C3a水平升高，并且在哮喘急性发作期间进一步升高。但是，人们对C3a对变应原致敏的作用了解甚少。对真菌过敏原（如烟曲霉）的致敏作用是哮喘发展的重要危险因素。暴露于几丁质是真菌细胞壁的一种结构多糖，可诱发先天性过敏性炎症，并可能促进对真菌过敏原的敏感性。在这里，我们发现几丁质与小鼠血清或气管内给予几丁质共孵育导致了C3a的产生。我们建立了对可溶性曲霉抗原的几丁质依赖性致敏模型，以测试补体对这些事件的贡献。保护C3 ？/？和C3aR ？/？小鼠免受甲壳质对曲霉菌的致敏作用，并减少肺嗜酸性粒细胞增多和2型细胞因子和血清IgE。相反，缺乏补体的小鼠不能抵抗几丁质诱导的先天性过敏性炎症。在致敏小鼠中，补体缺陷型动物的浆细胞样树突状细胞具有与增强的调节性T细胞反应相关的致耐受性，并抑制了曲霉特异的Th2和Th17反应。因此，几丁质诱导肺中C3a的生成，几丁质对曲霉的过敏性增敏需要C3aR信号传导，从而抑制调节性树突状细胞和T细胞，并诱导促进过敏的T细胞。 >重要：哮喘是全球增长最快的慢性疾病之一。甲壳素是我们环境中的一种普遍存在的聚合物，是真菌孢子和昆虫，寄生虫和甲壳类动物的外骨骼的细胞壁中的关键成分，可引发先天性过敏性炎症。然而，对于哺乳动物最初如何识别几丁质以及几丁质的早期识别如何影响对环境变应原的致敏性和过敏性哮喘的发展还知之甚少。补体系统在进化上是哺乳动物早期或先天预警系统中最古老的方面之一。我们研究了补体成分是否以及如何影响甲壳素的识别，并塑造了对真菌过敏原的下游敏感性。我们在这里显示，几丁质的补体识别在塑造树突状细胞的行为中起关键作用，而树突状细胞又调节介导对真菌的过敏反应的T细胞的功能。

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