Interleukin-1α Is a Critical Mediator of the Response of Human Bronchial Fibroblasts to Eosinophilic Inflammation.

Ksenija Bernau,Andrea L Noll,Nathan Sandbo,Jonathan P Leet,Ivy S Mcdermott,Nizar N Jarjour,Ellen M Bruhn,Stephane Esnault,Heather Floerke

doi:10.3390/cells10030528

Abstract

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.

Highlights

Eosinophilic inflammation is a hallmark of allergic asthma
We have found that upon stimulation with eosinophil soluble mediators, Human bronchial fibroblasts (HBF) are activated through IL1 receptor (IL1R) by IL1α, but not IL1β, leading to the activation of divergent intracellular signaling pathways that lead to the release of interleukin 6 (IL6) and interleukin 8 (IL8)
We have previously identified the release of IL1β from activated eosinophils [25,26], which could account for paracrine signaling in the asthmatic airway

Summary

Introduction

Eosinophilic inflammation is a hallmark of allergic asthma. Eosinophil presence in the asthmatic airway is associated with increased disease severity and risk of exacerbations [1,2]. Airway eosinophils contribute to allergic inflammation in asthma by releasing a variety of soluble mediators and cell-free granule proteins through cytolysis and degranulation [3,4,5] These factors contribute to the pro-inflammatory activation of other cell types, including bronchial fibroblasts, resulting in prolonged tissue injury that can lead to airway remodeling and subsequent irreversible airflow obstruction in some subjects [6,7,8]. Previous studies have typically utilized approaches where identified eosinophil-derived mediators are tested in isolation to observe effects on secondary structural cell cultures While these studies have led to a critical mechanistic understanding of potential signaling that may result from these mediators, it is unclear how the milieu of the released products by eosinophils affects bronchial fibroblasts in aggregate

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Discussion

Conclusion