Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease with an unknown etiology. Recent studies have implicated the complement system as a potential modulator of disease immunopathology. We performed proteomic pathway enrichment analysis of differentially increased proteins, and found an enrichment of complement cascade pathways in the nasal mucus of individuals with CRSwNP as compared to control subjects. Sinonasal mucus levels of complement 3 (C3) correlated with worse subjective disease severity, whereas no significant difference in systemic C3 levels could be determined in plasma samples. Given that human sinonasal epithelial cells were the predominate sinonasal source of C3 and complement anaphylatoxin 3a (C3a) staining, we focused on their role in in vitro studies. Baseline intracellular C3 levels were higher in CRSwNP cells, and following exposure to Aspergillus fumigatus (Af) extract, they released significantly more C3 and C3a. Inhibition of complement 3a receptor (C3aR) signaling led to a decrease in Af-induced C3 and C3a release, both in vitro and in vivo. Finally, we found in vivo that C3aR deficiency or inhibition significantly reduced inflammation and CRS development in a mouse model of Af-induced CRS. These findings demonstrate that local sinonasal complement activation correlates with subjective disease severity, and that local C3aR antagonism significantly ameliorates Af-induced CRS in a rodent model.

中文翻译：

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C3a 受体拮抗剂作为慢性鼻鼻窦炎的新治疗靶点。

慢性鼻窦炎伴鼻息肉（CRSwNP）是一种病因不明的炎症性疾病。最近的研究表明补体系统是疾病免疫病理学的潜在调节剂。我们对差异增加的蛋白质进行了蛋白质组通路富集分析，发现与对照受试者相比，CRSwNP 个体的鼻粘液中补体级联通路富集。鼻腔粘液中补体 3 (C3) 的水平与较差的主观疾病严重程度相关，而血浆样本中的全身 C3 水平没有显着差异。鉴于人鼻腔上皮细胞是 C3 和补体过敏毒素 3a (C3a) 染色的主要鼻腔来源，我们重点关注它们在体外研究中的作用。CRSwNP 细胞的细胞内 C3 基线水平较高，接触烟曲霉 (Af) 提取物后，它们释放出显着更多的 C3 和 C3a。在体外和体内，补体 3a 受体 (C3aR) 信号传导的抑制导致 Af 诱导的 C3 和 C3a 释放减少。最后，我们在体内发现 C3aR 缺乏或抑制可显着减少 Af 诱导的 CRS 小鼠模型中的炎症和 CRS 发展。这些发现表明，局部鼻腔补体激活与主观疾病严重程度相关，并且局部 C3aR 拮抗作用可显着改善啮齿动物模型中 Af 诱导的 CRS。