REVIEW Airway epithelial regulation of pulmonary immune homeostasis and inflammation Teal S. Hallstrand a , ⁎ , 1 , Tillie L. Hackett b , 1 , William A. Altemeier a , Gustavo Matute-Bello a , Philip M. Hansbro c , Darryl A. Knight c a Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA b Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada c School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia Received 19 October 2013; accepted with revision 4 December 2013 Available online 14 December 2013 KEYWORDS Asthma; Epithelium; Chemokine; Chronic-obstructive pulmonary disease; Host defense; Tight junctions Abstract Recent genetic, structural and functional studies have identified the airway and lung epithelium as a key orchestrator of the immune response. Further, there is now strong evidence that epithelium dysfunction is involved in the development of inflammatory disorders of the lung. Here we review the characteristic immune responses that are orchestrated by the epithelium in response to diverse triggers such as pollutants, cigarette smoke, bacterial peptides, and viruses. We focus in part on the role of epithelium-derived interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), as well as CC family chemokines as critical regulators of the immune response. We cite examples of the function of the epithelium in host defense and the role of epithelium dysfunction in the development of inflammatory diseases. © 2014 Elsevier Inc. All rights reserved. Abbreviations: AAM, alternatively activated macrophage; AEC, airway epithelial cell; AHR, airway hyperresponsiveness; AJ, adherens junction; CARD, caspase recruitment and activation domain; CPA3, carboxypeptidase A3; DAMP, damage associated molecular pattern(s); DC, dendritic cell; EMCV, encephalomyocarditis virus; HNP, human neutrophil defensin; FLG, filaggrin; HDM, house dust mite; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; IL, interleukin; JAM, junction adhesion molecule; KLRG1, killer cell lectin-like receptor G1; MAPK, mitogen activated protein kinase; LDL, low density lipoprotein(s); MC, mast cell; MDA5, melanoma differentiation-associated protein 5; MID1, midline 1; NK, natural killer; NLR, NOD-like receptor; PAMP, pathogen-associated molecular pattern(s); PAR, protease-activated receptors; PRR, pattern-recognition receptor(s); RIG-I, retinoic acid-inducible gene 1; RLR, RIG-I-like receptor; RORA, retinoic acid-related orphan receptor α; RSV, respiratory syncytial virus; RV, rhinovirus; SP-C, surfactant protein C; STAT, signal transducer and activator of transcription; TJ, tight junction; TLR, Toll-like receptor; Treg, regulatory T cell; TSLP, thymic stromal lymphopoietin; TSLPR, TSLP receptor; ZO, zonular occluden. ⁎ Corresponding author at: Pulmonary and Critical Care Medicine, University of Washington, Box 356522, 1959 NE Pacific Street, Seattle, WA 98195-6522, USA. Fax: + 1 206 685 8673. E-mail address: tealh@uw.edu (T.S. Hallstrand). 1 Denotes co-first author. 1521-6616/$ - see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clim.2013.12.003 available at www.sciencedirect.com Clinical Immunology www.elsevier.com/locate/yclim Clinical Immunology (2014) 151,1–15