Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?

Abstract

@ERSpublicationsInterleukin-1 alpha released by airway epithelial cells may instruct fibroblasts to become proinflammatory in COPD http://ow.ly/CLYK301tyOjThe lungs are continuously exposed to inhaled particles and irritants. Tobacco smoking is the leading cause of several airway diseases, including lung cancer, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). In COPD, repeated exposure to cigarette smoke induces chronic inflammation and structural remodelling of the airways, with peribronchial fibrosis and epithelial-to-mesenchymal transition [1], resulting in (mostly irreversible) airway obstruction. Thus, abnormal airway responses to noxious gases probably results from aberrant signalling and crosstalk between epithelial, mesenchymal and immune cells.In this issue of the European Respiratory Journal, OSEI et al.[2] describe how epithelial cells signal to fibroblasts through interleukin (IL)-1α, with relevance to COPD. Using co-cultures of human primary cells (bronchial epithelial cells (BECs) and lung fibroblasts) and human cell lines (MRC5 fetal fibroblasts and 16HBE epithelial cells), the authors show that co-culture of BECs and fibroblasts induced the production of heat shock protein (Hsp)70, IL-8/CXCL8 and IL-1β by lung fibroblasts, while decreasing expression of α-smooth muscle actin, transforming growth factor (TGF)-β1 and extracellular matrix proteins. These effects, which were not different between control-and COPD-derived cells, were recapitulated by using BEC (16HBE)-conditioned medium, suggesting the requirement for soluble factor(s). Using neutralising antibodies, the authors went on to demonstrate that release of CXCL8 and Hsp70 by fibroblasts in the co-culture system was independent of IL-1β and prostaglandin E2 but dependent on IL-1α. In addition, IL-1α release by BECs was enhanced in COPD-derived cells by exposure to cigarette smoke extract. Although this in vitro model may not completely recapitulate the in vivo situation, it provides important new insights regarding the signals delivered by airway epithelial cells and regulating mesenchymal cells.There is accumulating evidence that BECs are key cells in frontline defence that directly signal to immune cells, in particular antigen-presenting cells [3,4]. Several previous works identified that BECs shape the immune response engaged by pathogens [5]. For instance, BECs exposed to Klebsiella pneumoniae regulate local immune responses notably by acting on the myeloid dendritic cell network [6]. Respiratory syncytial virus-infected BECs regulate CD8 + T-cell activation and antiviral activity, according to changes in epithelial expression of the "checkpoint" immune receptor PD-L1 [7]. BECs also regulate dendritic cell differentiation and maturation as well as responsiveness to lipopolysaccharide [8], and inhibit T-cell recall responses towards common aeroallergens in order to ensure mucosal homeostasis and dampen allergic responses [9]. It has also been shown in asthma that BECs may suppress constitutive and IgE-depen...

<p>Epithelial–mesenchymal transition is driven by transcriptional and post transcriptional modulations in COPD: implications for disease progression and new therapeutics</p>

“…They further found that urokinase plasminogen activation receptor could be responsible for modulating EMT, positively correlating with an increase in vimentin expression in human small airways 40. Recent in vitro epithelial–fibroblast co-culture studies also examined the probable role of IL-1α in promoting EMT 41. They reported that IL-1α caused aberrant epithelial–fibroblast interactions when stimulated by CSE 42…”