Abstract
Asthma is a T lymphocyte–controlled disease of the airway wall caused by inflammation, overproduction of mucus and airway wall remodeling leading to bronchial hyperreactivity and airway obstruction. The airway epithelium is considered an essential controller of inflammatory, immune and regenerative responses to allergens, viruses and environmental pollutants that contribute to asthma pathogenesis. Epithelial cells express pattern recognition receptors that detect environmental stimuli and secrete endogenous danger signals, thereby activating dendritic cells and bridging innate and adaptive immunity. Improved understanding of the epithelium's function in maintaining the integrity of the airways and its dysfunction in asthma has provided important mechanistic insight into how asthma is initiated and perpetuated and could provide a framework by which to select new therapeutic strategies that prevent exacerbations and alter the natural course of the disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Anderson, G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107–1119 (2008).
Bousquet, J. et al. Eosinophilic inflammation in asthma. N. Engl. J. Med. 323, 1033–1039 (1990).
Robinson, D.S. et al. Predominant TH2-like bronchoalveolar T lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
Choy, D.F. et al. Gene expression patterns of TH2 inflammation and intercellular communication in asthmatic airways. J. Immunol. 186, 1861–1869 (2011).
Lloyd, C.M. & Hessel, E.M. Functions of T cells in asthma: more than just TH2 cells. Nat. Rev. Immunol. 10, 838–848 (2010).
Woodruff, P.G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009).
Nair, P. et al. N. Engl. J. Med. 360, 985–993 (2009).
Wang, Y.H. et al. A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J. Exp. Med. 207, 2479–2491 (2010).
Tourdot, S. et al. Respiratory syncytial virus infection provokes airway remodelling in allergen-exposed mice in absence of prior allergen sensitization. Clin. Exp. Allergy 38, 1016–1024 (2008).
van Rijt, L.S. et al. Persistent activation of dendritic cells after resolution of allergic airway inflammation breaks tolerance to inhaled allergens in mice. Am. J. Respir. Crit. Care Med. 184, 303–311 (2011).
Xiao, C. et al. Defective epithelial barrier function in asthma. J. Allergy Clin. Immunol. 128, 549–556.e1–12 (2011).
Lambrecht, B.N. & Hammad, H. Biology of lung dendritic cells at the origin of asthma. Immunity 31, 412–424 (2009).
Sung, S.S. et al. A major lung CD103 (αE)-β7 integrin–positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J. Immunol. 176, 2161–2172 (2006).
Lambrecht, B.N. & Hammad, H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu. Rev. Immunol. 30, 243–270 (2012).
Hammad, H. et al. Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of TH2 immunity to inhaled house dust mite allergen. J. Exp. Med. 207, 2097–2111 (2010).
van Rijt, L.S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).
Hammad, H. et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15, 410–416 (2009).
Tan, A.M. et al. TLR4 signaling in stromal cells is critical for the initiation of allergic TH2 responses to inhaled antigen. J. Immunol. 184, 3535–3544 (2010).
Trompette, A. et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585–588 (2009).
Guillot, L. et al. Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J. Biol. Chem. 279, 2712–2718 (2004).
Jia, H.P. et al. Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L428–L437 (2004).
Pace, E. et al. Cigarette smoke increases Toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells. Immunology 124, 401–411 (2008).
Monick, M.M. et al. Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. J. Biol. Chem. 278, 53035–53044 (2003).
Poynter, M.E., Irvin, C.G. & Janssen-Heininger, Y.M.W. Rapid activation of nuclear factor-κB in airway epithelium in a murine model of allergic airway inflammation. Am. J. Pathol. 160, 1325–1334 (2002).
Yang, L. et al. Essential role of nuclear factor κB in the induction of eosinophilia in allergic airway inflammation. J. Exp. Med. 188, 1739–1750 (1998).
Ather, J.L., Hodgkins, S.R., Janssen-Heininger, Y.M. & Poynter, M.E. Airway epithelial NF-κB activation promotes allergic sensitization to an innocuous inhaled antigen. Am. J. Respir. Cell Mol. Biol. 44, 631–638 (2011).
Broide, D.H. et al. Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase-β–dependent genes in airway epithelium. Proc. Natl. Acad. Sci. USA 102, 17723–17728 (2005).
Kelly, C., Shields, M.D., Elborn, J.S. & Schock, B.C. A20 regulation of nuclear factor-κB: perspectives for inflammatory lung disease. Am. J. Respir. Cell Mol. Biol. 44, 743–748 (2011).
Kool, M. et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 35, 82–96 (2011).
El Bakkouri, K., Wullaert, A., Haegman, M., Heyninck, K. & Beyaert, R. Adenoviral gene transfer of the NF-κB inhibitory protein ABIN-1 decreases allergic airway inflammation in a murine asthma model. J. Biol. Chem. 280, 17938–17944 (2005).
Rate, A., Upham, J.W., Bosco, A., McKenna, K.L. & Holt, P.G. Airway epithelial cells regulate the functional phenotype of locally differentiating dendritic cells: implications for the pathogenesis of infectious and allergic airway disease. J. Immunol. 182, 72–83 (2009).
Nathan, A.T., Peterson, E.A., Chakir, J. & Wills-Karp, M. Innate immune responses of airway epithelium to house dust mite are mediated through β-glucan–dependent pathways. J. Allergy Clin. Immunol. 123, 612–618 (2009).
Walter, M.J., Kajiwara, N., Karanja, P., Castro, M. & Holtzman, M.J. Interleukin-12 p40 production by barrier epithelial cells during airway inflammation. J. Exp. Med. 193, 339–352 (2001).
Ramadas, R.A., Ewart, S.L., Medoff, B.D. & LeVine, A.M. Interleukin-1–family member 9 stimulates chemokine production and neutrophil influx in mouse lungs. Am. J. Respir. Cell Mol. Biol. 44, 134–145 (2011).
Chustz, R.T. et al. Regulation and function of the IL-1 family cytokine IL-1F9 in human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 45, 145–153 (2011).
Vigne, S. et al. IL-36R ligands are potent regulators of dendritic and T cells. Blood 118, 5813–5823 (2011).
Besnard, A.G. et al. IL-33–activated dendritic cells are critical for allergic airway inflammation. Eur. J. Immunol. 41, 1675–1686 (2011).
Rank, M.A. et al. IL-33–activated dendritic cells induce an atypical TH2-type response. J. Allergy Clin. Immunol. 123, 1047–1054 (2009).
Lambrecht, B.N. et al. Myeloid dendritic cells induce TH2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106, 551–559 (2000).
Préfontaine, D. et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J. Allergy Clin. Immunol. 125, 752–754 (2010).
Wang, Y.H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC–activated TH2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).
Angkasekwinai, P. et al. Interleukin-25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).
Goswami, S. et al. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat. Immunol. 10, 496–503 (2009).
Kaiko, G.E., Phipps, S., Angkasekwinai, P., Dong, C. & Foster, P.S. NK cell deficiency predisposes to viral-induced TH2-type allergic inflammation via epithelial-derived IL-25. J. Immunol. 185, 4681–4690 (2010).
Stämpfli, M.R. et al. GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J. Clin. Invest. 102, 1704–1714 (1998).
Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).
Cates, E.C. et al. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF–mediated mechanism. J. Immunol. 173, 6384–6392 (2004).
Ohta, K. et al. Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF. J. Allergy Clin. Immunol. 104, 1024–1030 (1999).
Bleck, B., Tse, D.B., Jaspers, I., Curotto de Lafaille, M.A. & Reibman, J. Diesel exhaust particle–exposed human bronchial epithelial cells induce dendritic cell maturation. J. Immunol. 176, 7431–7437 (2006).
Ritz, S.A., Stampfli, M.R., Davies, D.E., Holgate, S.T. & Jordana, M. On the generation of allergic airway diseases: from GM-CSF to Kyoto. Trends Immunol. 23, 396–402 (2002).
Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of TH2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).
Semlali, A., Jacques, E., Koussih, L., Gounni, A.S. & Chakir, J. Thymic stromal lymphopoietin-induced human asthmatic airway epithelial cell proliferation through an IL-13–dependent pathway. J. Allergy Clin. Immunol. 125, 844–850 (2010).
Harada, M. et al. Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma. Am. J. Respir. Cell Mol. Biol. 44, 787–793 (2011).
Kouzaki, H., O'Grady, S.M., Lawrence, C.B. & Kita, H. Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2. J. Immunol. 183, 1427–1434 (2009).
Bleck, B., Tse, D.B., Gordon, T., Ahsan, M.R. & Reibman, J. Diesel exhaust particle-treated human bronchial epithelial cells upregulate Jagged-1 and OX40 ligand in myeloid dendritic cells via thymic stromal lymphopoietin. J. Immunol. 185, 6636–6645 (2010).
Reardon, C. et al. Thymic stromal lymphopoetin-induced expression of the endogenous inhibitory enzyme SLPI mediates recovery from colonic inflammation. Immunity 35, 223–235 (2011).
Marino, R. et al. Secretory leukocyte protease inhibitor plays an important role in the regulation of allergic asthma in mice. J. Immunol. 186, 4433–4442 (2011).
Fort, M.M. et al. IL-25 induces IL-4, IL-5, and IL-13 and TH2-associated pathologies in vivo. Immunity 15, 985–995 (2001).
Schneider, E. et al. IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting hematopoietic growth factor production. J. Immunol. 183, 3591–3597 (2009).
Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Saenz, S.A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).
Siracusa, M.C. et al. TSLP promotes interleukin-3–independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229–233 (2011).
Chang, Y.J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).
Monticelli, L.A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).
Matsukura, S. et al. Interleukin-13 upregulates eotaxin expression in airway epithelial cells by a STAT6-dependent mechanism. Am. J. Respir. Cell Mol. Biol. 24, 755–761 (2001).
Lordan, J.L. et al. Cooperative effects of TH2 cytokines and allergen on normal and asthmatic bronchial epithelial cells. J. Immunol. 169, 407–414 (2002).
Mitchell, C., Provost, K., Niu, N., Homer, R. & Cohn, L. IFN-γ acts on the airway epithelium to inhibit local and systemic pathology in allergic airway disease. J. Immunol. 187, 3815–3820 (2011).
Kool, M. et al. An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34, 527–540 (2011).
Idzko, M. et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat. Med. 13, 913–919 (2007).
Müller, T. et al. The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation. Allergy 65, 1545–1553 (2010).
Boldogh, I. et al. ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J. Clin. Invest. 115, 2169–2179 (2005).
Rangasamy, T. et al. Nuclear erythroid 2 p45-related factor 2 inhibits the maturation of murine dendritic cells by ragweed extract. Am. J. Respir. Cell Mol. Biol. 43, 276–285 (2010).
Ckless, K., Hodgkins, S.R., Ather, J.L., Martin, R. & Poynter, M.E. Epithelial, dendritic, and CD4+ T cell regulation of and by reactive oxygen and nitrogen species in allergic sensitization. Biochim. Biophys. Acta 1810, 1025–1034 (2011).
Kim, S.R. et al. HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. Eur. J. Immunol. 40, 2858–2869 (2010).
Lee, C.G. et al. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat. Med. 10, 1095–1103 (2004).
Medoff, B.D. et al. CARMA3 mediates lysophosphatidic acid–stimulated cytokine secretion by bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 40, 286–294 (2009).
Liang, J. et al. Role of hyaluronan and hyaluronan-binding proteins in human asthma. J. Allergy Clin. Immunol. 128, 403–411.3 (2011).
Schmidt, L.M. et al. Bronchial epithelial cell–derived prostaglandin E2 dampens the reactivity of dendritic cells. J. Immunol. 186, 2095–2105 (2011).
Karp, C.L. et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat. Immunol. 5, 388–392 (2004).
Xu, J., Park, P.W., Kheradmand, F. & Corry, D.B. Endogenous attenuation of allergic lung inflammation by syndecan-1. J. Immunol. 174, 5758–5765 (2005).
Nold, M.F. et al. IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 11, 1014–1022 (2010).
Mattes, J., Collison, A., Plank, M., Phipps, S. & Foster, P.S. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc. Natl. Acad. Sci. USA 106, 18704–18709 (2009).
Wan, H. et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J. Clin. Invest. 104, 123–133 (1999).
Lackie, P.M., Baker, J.E., Gunthert, U. & Holgate, S.T. Expression of CD44 isoforms is increased in the airway epithelium of asthmatic subjects. Am. J. Respir. Cell Mol. Biol. 16, 14–22 (1997).
Hackett, T.L. et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-β1. Am. J. Respir. Crit. Care Med. 180, 122–133 (2009).
de Boer, W.I. et al. Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation. Can. J. Physiol. Pharmacol. 86, 105–112 (2008).
Nawijn, M.C., Hackett, T.L., Postma, D.S., van Oosterhout, A.J. & Heijink, I.H. E-cadherin: gatekeeper of airway mucosa and allergic sensitization. Trends Immunol. 32, 248–255 (2011).
Jiang, A. et al. Disruption of E-cadherin–mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007).
Heijink, I.H. et al. Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor–dependent TH2 cell–promoting activity. J. Immunol. 178, 7678–7685 (2007).
Koppelman, G.H. et al. Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness. Am. J. Respir. Crit. Care Med. 180, 929–935 (2009).
Antony, A.B., Tepper, R.S. & Mohammed, K.A. Cockroach extract antigen increases bronchial airway epithelial permeability. J. Allergy Clin. Immunol. 110, 589–595 (2002).
Runswick, S., Mitchell, T., Davies, P., Robinson, C. & Garrod, D.R. Pollen proteolytic enzymes degrade tight junctions. Respirology 12, 834–842 (2007).
Chen, J.C. et al. The protease allergen Pen c 13 induces allergic airway inflammation and changes in epithelial barrier integrity and function in a murine model. J. Biol. Chem. 286, 26667–26679 (2011).
Olivera, D.S., Boggs, S.E., Beenhouwer, C., Aden, J. & Knall, C. Cellular mechanisms of mainstream cigarette smoke–induced lung epithelial tight junction permeability changes in vitro. Inhal. Toxicol. 19, 13–22 (2007).
Rezaee, F. et al. Polyinosinic:polycytidylic acid induces protein kinase D–dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells. J. Allergy Clin. Immunol. 128, 1216–1224.e11 (2011).
Heijink, I.H., van Oosterhout, A. & Kapus, A. Epidermal growth factor receptor signalling contributes to house dust mite–induced epithelial barrier dysfunction. Eur. Respir. J. 36, 1016–1026 (2010).
Sidhaye, V.K., Chau, E., Breysse, P.N. & King, L.S. Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions. Am. J. Respir. Cell Mol. Biol. 45, 120–126 (2011).
Ahdieh, M., Vandenbos, T. & Youakim, A. Lung epithelial barrier function and wound healing are decreased by IL-4 and IL-13 and enhanced by IFN-γ. Am. J. Physiol. Cell Physiol. 281, C2029–C2038 (2001).
Flood-Page, P. et al. Anti–IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 112, 1029–1036 (2003).
Le Cras, T.D. et al. Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L414–L421 (2011).
Holgate, S.T. et al. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J. Allergy Clin. Immunol. 105, 193–204 (2000).
Sidhu, S.S. et al. Roles of epithelial cell–derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. Proc. Natl. Acad. Sci. USA 107, 14170–14175 (2010).
Song, D.J. et al. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J. Immunol. 183, 5333–5341 (2009).
Doherty, T.A. et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat. Med. 17, 596–603 (2011).
Cho, J.Y. et al. Chronic OVA allergen challenged TNF p55/p75 receptor deficient mice have reduced airway remodeling. Int. Immunopharmacol. 11, 1038–1044 (2011).
Lee, S.H., Eren, M., Vaughan, D.E., Schleimer, R.P. & Cho, S.A. PAI-1 inhibitor reduces airway remodeling in a murine model of chronic asthma. Am. J. Respir. Cell Mol. Biol. doi: 10.1165/rcmb.2011-0369O (2012).
Saglani, S. et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am. J. Respir. Crit. Care Med. 176, 858–864 (2007).
Malmström, K. et al. Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years. Thorax 66, 157–162 (2011).
Hackett, T.L. et al. Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to RSV and air pollution. Am. J. Respir. Cell Mol. Biol. 45, 1090–1100 (2011).
Puddicombe, S.M. et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 14, 1362–1374 (2000).
Enomoto, Y. et al. Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack. J. Allergy Clin. Immunol. 124, 913–920.e1–7 (2009).
Royce, S.G., Lim, C., Muljadi, R.C. & Tang, M.L. Trefoil factor 2 regulates airway remodeling in animal models of asthma. J. Asthma 48, 653–659 (2011).
Dabbagh, K. et al. IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J. Immunol. 162, 6233–6237 (1999).
Kuperman, D.A. et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 8, 885–889 (2002).
Wills-Karp, M. et al. Interleukin-13: Central mediator of allergic asthma. Science 282, 2258–2261 (1998).
Hirota, N. et al. Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells. FASEB J. 26, 1704–1716 (1998).
Chen, G. et al. Foxa2 programs TH2 cell–mediated innate immunity in the developing lung. J. Immunol. 184, 6133–6141 (2010).
Gregorieff, A. et al. The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium. Gastroenterology 137, 1333–1345.e1–3 (2009).
Hasnain, S.Z., Thornton, D.J. & Grencis, R.K. Changes in the mucosal barrier during acute and chronic Trichuris muris infection. Parasite Immunol. 33, 45–55 (2011).
Phythian-Adams, A.T. et al. CD11c depletion severely disrupts TH2 induction and development in vivo. J. Exp. Med. 207, 2089–2096 (2010).
Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).
Martino, M.E. et al. Airway epithelial inflammation-induced endoplasmic reticulum Ca2+ store expansion is mediated by X-box–binding protein-1. J. Biol. Chem. 284, 14904–14913 (2009).
Martinon, F., Chen, X., Lee, A.H. & Glimcher, L.H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418 (2010).
Moffatt, M.F. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007).
Cantero-Recasens, G., Fandos, C., Rubio-Moscardo, F., Valverde, M.A. & Vicente, R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum. Mol. Genet. 19, 111–121 (2010).
Busse, W.W., Lemanske, R.F. Jr. & Gern, J.E. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet 376, 826–834 (2010).
Wark, P.A. et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201, 937–947 (2005).
Contoli, M. et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nat. Med. 12, 1023–1026 (2006).
Moriwaki, A. et al. IL-13 suppresses double-stranded RNA-induced IFN-λ production in lung cells. Biochem. Biophys. Res. Commun. 404, 922–927 (2011).
Koltsida, O. et al. IL-28A (IFN-λ2) modulates lung DC function to promote TH1 immune skewing and suppress allergic airway disease. EMBO Mol. Med. 3, 348–361 (2011).
Agresti, A., Lupo, R., Bianchi, M.E. & Muller, S. HMGB1 interacts differentially with members of the Rel family of transcription factors. Biochem. Biophys. Res. Commun. 302, 421–426 (2003).
Torres, D. et al. Double-stranded RNA exacerbates pulmonary allergic reaction through TLR3: implication of airway epithelium and dendritic cells. J. Immunol. 185, 451–459 (2010).
Monick, M.M. et al. Respiratory syncytial virus synergizes with TH2 cytokines to induce optimal levels of TARC/CCL17. J. Immunol. 179, 1648–1658 (2007).
Woodruff, P.G. et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Natl. Acad. Sci. USA 104, 15858–15863 (2007).
Xirakia, C. et al. Toll-like receptor 7–triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma. Am. J. Respir. Crit. Care Med. 181, 1207–1216 (2010).
Song, D.J. et al. Toll-like receptor 9 agonist inhibits airway inflammation, remodeling and hyperreactivity in mice exposed to chronic environmental tobacco smoke and allergen. Int. Arch. Allergy Immunol. 151, 285–296 (2010).
Hertz, C.J. et al. Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human β-defensin 2. J. Immunol. 171, 6820–6826 (2003).
Sha, Q., Truong-Tran, A.Q., Plitt, J.R., Beck, L.A. & Schleimer, R.P. Activation of airway epithelial cells by Toll-like receptor agonists. Am. J. Respir. Cell Mol. Biol. 31, 358–364 (2004).
Saito, T., Yamamoto, T., Kazawa, T., Gejyo, H. & Naito, M. Expression of Toll-like receptor 2 and 4 in lipopolysaccharide-induced lung injury in mouse. Cell Tissue Res. 321, 75–88 (2005).
Uehara, A., Fujimoto, Y., Fukase, K. & Takada, H. Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol. Immunol. 44, 3100–3111 (2007).
Kool, M. et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).
Eisenbarth, S.C., Colegio, O.R., O'Connor, W., Sutterwala, F.S. & Flavell, R.A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).
Ather, J.L. et al. Serum amyloid A activates the NLRP3 inflammasome and promotes TH17 allergic asthma in mice. J. Immunol. 187, 64–73 (2011).
Provoost, S. et al. NLRP3/caspase-1–independent IL-1β production mediates diesel exhaust particle-induced pulmonary inflammation. J. Immunol. 187, 3331–3337 (2011).
Finkelman, M.A., Lempitski, S.J. & Slater, J.E. β-glucans in standardized allergen extracts. J. Endotoxin Res. 12, 241–245 (2006).
Barrett, N.A. et al. Dectin-2 mediates TH2 immunity through the generation of cysteinyl leukotrienes. J. Exp. Med. 208, 593–604 (2011).
Adam, E. et al. The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2–independent mechanism. J. Biol. Chem. 281, 6910–6923 (2006).
Pichavant, M. et al. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. J. Allergy Clin. Immunol. 115, 771–778 (2005).
Tomee, J.F., van Weissenbruch, R., de Monchy, J.G. & Kauffman, H.F. Interactions between inhalant allergen extracts and airway epithelial cells: effect on cytokine production and cell detachment. J. Allergy Clin. Immunol. 102, 75–85 (1998).
Page, K., Ledford, J.R., Zhou, P., Dienger, K. & Wills-Karp, M. Mucosal sensitization to German cockroach involves protease-activated receptor-2. Respir. Res. 11, 62 (2010).
Whitsett, J.A., Haitchi, H.M. & Maeda, Y. Intersections between pulmonary development and disease. Am. J. Respir. Crit. Care Med. 184, 401–406 (2011).
Volckaert, T. et al. Parabronchial smooth muscle constitutes an airway epithelial stem-cell niche in the mouse lung after injury. J. Clin. Invest. 121, 4409–4419 (2011).
Sivaprasad, U. et al. A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma. J. Allergy Clin. Immunol. 127, 254–261 (2011).
Park, K.S. et al. SPDEF regulates goblet cell hyperplasia in the airway epithelium. J. Clin. Invest. 117, 978–988 (2007).
Chen, G. et al. SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. J. Clin. Invest. 119, 2914–2924 (2009).
Maeda, Y. et al. Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and TH2 inflammation. Am. J. Respir. Crit. Care Med. 184, 421–429 (2011).
Acknowledgements
B.N.L. is a recipient of an Odysseus Grant of the Flemish Organization for Scientific Research (FWO) and recipient of an ERC Consolidator grant and a UGent Multidisciplinary Research Partnership grant (Group-ID). H.H. and B.N.L. are supported by National Institutes of Health grant 5R21AI083690-02. H.H. is a recipient of an FWO program grant.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Lambrecht, B., Hammad, H. The airway epithelium in asthma. Nat Med 18, 684–692 (2012). https://doi.org/10.1038/nm.2737
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2737
This article is cited by
-
Akebia saponin D attenuates allergic airway inflammation through AMPK activation
Journal of Natural Medicines (2024)
-
LncRNA AK089514/miR-125b-5p/TRAF6 axis mediates macrophage polarization in allergic asthma
BMC Pulmonary Medicine (2023)
-
Rhinovirus infection induces secretion of endothelin-1 from airway epithelial cells in both in vitro and in vivo models
Respiratory Research (2023)
-
Activation of NLRP3 inflammasome in lung epithelial cells triggers radiation-induced lung injury
Respiratory Research (2023)
-
Rhinovirus induces airway remodeling: what are the physiological consequences?
Respiratory Research (2023)