Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
Cells. 2021 Mar 2;10(3):528. doi: 10.3390/cells10030528.
Eosinophils contribute to allergic inflammation in asthma in part via elaboration of a complex milieu of soluble mediators. Human bronchial fibroblasts (HBF) respond to stimulation by these mediators by acquiring a pro-inflammatory profile including induction of interleukin 6 (IL6) and IL8. This study sought to determine key component(s) of eosinophil soluble factors that mediate IL6 and IL8 induction in HBF. HBF treated with eosinophil-derived soluble mediators were analyzed for gene expression, intracellular signaling, and IL6 and IL8 secretion following inhibition of inflammatory signaling. Segmental allergen bronchoprovocation (SBP-Ag) was performed in mild asthmatics and bronchoalveolar lavage fluid was analyzed for eosinophils and cytokines. We found that signaling via the IL1α/IL1 receptor is an essential component of the response of HBF to eosinophil-derived soluble factors. IL1α-dependent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling is required to induce IL6 secretion. However, NFκB signaling is dispensable for the induction of IL8, whereas Src is required. IL1α is associated with eosinophilic inflammation in human airways after SBP-Ag. Conclusions: IL1α appears to be a critical component of the soluble eosinophil-derived milieu that drives pro-inflammatory bronchial fibroblast responses and associates with eosinophilic inflammation following SBP-Ag. Disruption of IL1α-signaling could modify the downstream effects of eosinophilic inflammation on airway remodeling.
嗜酸性粒细胞通过分泌大量可溶性介质在哮喘的变应性炎症中发挥作用。这些介质可刺激人支气管成纤维细胞(HBF)获得促炎表型,包括诱导白细胞介素 6(IL6)和白细胞介素 8(IL8)的表达。本研究旨在确定介导 HBF 中 IL6 和 IL8 诱导的嗜酸性粒细胞可溶性因子的关键成分。用嗜酸性粒细胞衍生的可溶性介质处理 HBF 后,通过抑制炎症信号转导分析基因表达、细胞内信号转导以及 IL6 和 IL8 的分泌。对轻度哮喘患者进行分段变应原支气管激发(SBP-Ag),并分析支气管肺泡灌洗液中的嗜酸性粒细胞和细胞因子。结果发现,IL1α/IL1 受体信号转导是 HBF 对嗜酸性粒细胞衍生的可溶性因子反应的重要组成部分。IL1α 依赖性核因子 kappa 轻链增强子的 B 细胞(NFκB)信号转导的激活对于诱导 IL6 分泌是必需的。然而,NFκB 信号转导对于 IL8 的诱导是可有可无的,而 Src 是必需的。在 SBP-Ag 后,IL1α 与人类气道中的嗜酸性粒细胞炎症相关。结论:IL1α 似乎是驱动促炎性支气管成纤维细胞反应的嗜酸性粒细胞衍生的可溶性微环境的关键成分,并与 SBP-Ag 后嗜酸性粒细胞炎症相关。阻断 IL1α 信号转导可能会改变嗜酸性粒细胞炎症对气道重塑的下游影响。