title: IL-1α mediates cellular cross-talk in the airway epithelial mesenchymal trophic unit.
abstract: The bronchial epithelium and underlying fibroblasts form an epithelial mesenchymal trophic unit (EMTU) which controls the airway microenvironment. We hypothesized that cell-cell communication within the EMTU propagates and amplifies the innate immune response to respiratory viral infections. EMTU co-culture models incorporating polarized (16HBE14o-) or differentiated primary human bronchial epithelial cells (HBECs) and fibroblasts were challenged with double-stranded RNA (dsRNA) or rhinovirus. In the polarized EMTU model, dsRNA affected ionic but not macromolecular permeability or cell viability. Compared with epithelial monocultures, dsRNA-stimulated pro-inflammatory mediator release was synergistically enhanced in the basolateral compartment of the EMTU model, with the exception of IL-1α which was unaffected by the presence of fibroblasts. Blockade of IL-1 signaling with IL-1 receptor antagonist (IL-1Ra) completely abrogated dsRNA-induced basolateral release of mediators except CXCL10. Fibroblasts were the main responders to epithelial-derived IL-1 since exogenous IL-1α induced pro-inflammatory mediator release from fibroblast but not epithelial monocultures. Our findings were confirmed in a differentiated EMTU model where rhinovirus infection of primary HBECs and fibroblasts resulted in synergistic induction of basolateral IL-6 that was significantly abrogated by IL-1Ra. This study provides the first direct evidence of integrated IL-1 signaling within the EMTU to propagate inflammatory responses to viral infection.
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton , Southampton, UK.
authors: Alison R
authors: AR
authors: Hill
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton , Southampton, UK.
authors: Jessica E
authors: JE
authors: Donaldson
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton , Southampton, UK.
authors: Cornelia
authors: C
authors: Blume
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton , Southampton, UK.
authors: Natalie
authors: N
authors: Smithers
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton , Southampton, UK.
authors: Liku
authors: L
authors: Tezera
authors: NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton , Southampton, UK.
authors: Kamran
authors: K
authors: Tariq
authors: NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton , Southampton, UK.
authors: Patrick
authors: P
authors: Dennison
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK; NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
authors: Hitasha
authors: H
authors: Rupani
authors: Novartis Institutes for BioMedical Research , Horsham, UK.
authors: Matthew J
authors: MJ
authors: Edwards
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK; NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
authors: Peter H
authors: PH
authors: Howarth
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton , Southampton, UK.
authors: Christopher
authors: C
authors: Grainge
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK; NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK; Institute for Life Sciences, Highfield Campus, University of Southampton, Southampton, UK.
authors: Donna E
authors: DE
authors: Davies
authors: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK; NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK; Institute for Life Sciences, Highfield Campus, University of Southampton, Southampton, UK.
authors: Emily J
authors: EJ
authors: Swindle
mesh_terms: D002199:Capillary Permeability; D002450:Cell Communication; D002460:Cell Line; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D054357:Chemokine CXCL10 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology; D005347:Fibroblasts / Q000378:metabolism* / Q000821:virology; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D012229:Rhinovirus / Q000472:pathogenicity; D015398:Signal Transduction
chemical_list: D054357:Chemokine CXCL10; D053582:Interleukin-1alpha
keywords: cross-talk; epithelial cells; fibroblasts; in vitro models of the airway; viral infection