Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

doi:10.1016/j.coi.2007.08.004

Current Opinion in Immunology

Volume 19, Issue 6, December 2007, Pages 711-720

https://doi.org/10.1016/j.coi.2007.08.004 Get rights and content

It has become increasingly clear that airway epithelial cells are central participants in innate and adaptive immune responses as well as mucosal inflammation. Epithelial cells produce antimicrobial host defense molecules, proinflammatory cytokines and chemokines in response to activation via pathogen recognition receptors. Recruitment of immune cells including dendritic cells, T cells and B cells into the proximity of epithelium results in the enhancement of adaptive immunity through interactions with epithelial cells. Newly identified epithelial-derived cytokines, including TSLP, IL-33 and BAFF, help to shape the local accumulation and activation of Th2 responses and B cell immunoglobulin production. Epithelial cells are also downstream targets of molecules that activate IL-13R and EGFR and are responsible for mucus production in both protective immune responses and allergic airway inflammatory diseases. Improved understanding of epithelial immune and inflammatory responses will hopefully suggest new strategies for therapeutic intervention.

Introduction

A long-recognized property of airway epithelial cells is their function as a complex physical barrier that defends against exposures to potentially harmful inhaled substances and microbial pathogens. It is now clear that airway epithelial cells also play crucial roles in initiating and augmenting airway host defense mechanisms. Epithelial cells, which are positioned at the line of first exposure to many pathogens, regulate both innate and adaptive immunity through production of functional molecules and via physical interactions with cells of the immune system. Activation of epithelial cells can result in immediate host defense responses that exclude pathogens, as they are induced to produce host defense molecules including antimicrobial and antiviral proteins along with proinflammatory cytokines that can activate other mucosal innate immune cells. Activation of the innate immune response secondarily induces recruitment of immune cells into epithelium to initiate adaptive immunity. By contrast, prolonged and/or robust epithelial activation can result in the release of large quantities of proinflammatory cytokines, growth factors and chemokines that attract inflammatory cells and that initiate and sustain airway inflammatory diseases such as asthma. The role of the airway epithelium in the pathogenesis of airway inflammatory diseases has been extensively studied and is well established.

Bronchial asthma is a classic Th2 disease that is characterized by prolonged epithelial activation associated with exposure to allergens to which the subject has been sensitized. Following activation by T cell cytokines, epithelial cells release large quantities of proinflammatory cytokines, growth factors and chemokines, amplifying the influx of T cells, eosinophils, basophils and other inflammatory cells. This inflammation results in the associated pathological features of airway hyper-responsiveness, hyperplasia/metaplasia of goblet cells and subepithelial fibrosis. The purpose of this review is to discuss several recently recognized functions of epithelial cells in innate and adaptive immune responses that go far beyond the inflammatory role of epithelial cells and to put them in the context of allergic airways disease. Emphasis will be placed on newly identified epithelial innate immune effector responses and regulation of the activation of dendritic cells (DC), T cells and B cells. Finally, we discuss two recently recognized pathways by which the products of infiltrating immune and inflammatory cells activate epithelial cells to induce pathogenic changes in allergic inflammation.

Section snippets

Epithelium and innate immune recognition

The mammalian immune system is comprised of two branches, the innate immune system and the adaptive immune system, that work in tandem to provide resistance to infection. The innate immune response is the first line of host defense and is responsible for immediate recognition and control of microbial invasion. The innate immune response relies on evolutionarily ancient germline-encoded receptors, the pattern-recognition receptors (PRRs), which recognize highly conserved microbial structures [1••

Epithelium and host defense

Airway epithelial cells secrete a host of molecules from several families that are involved in the protection against infection by bacteria, viruses and fungi. Major antimicrobial products secreted constitutively and/or inducibly by epithelial cells include lysozyme, lactoferrin, defensins, collectins, pentraxins, LL-37, secretory leukocyte protease inhibitor (SLPI) and serum amyloid A (SAA) (Figure 1) [13]. Mechanistically, these molecules can be divided into enzymes, permeabilizing peptides,

Interactions of epithelial cells with DC

Airway epithelial cells not only mediate and activate innate immune responses but also regulate adaptive immune responses through interactions with DC, T cells and B cells. Local and infiltrating DC have a vital role in the initiation of adaptive immune responses to inhaled foreign antigens. Airway epithelial cells are capable of inducing DC migration into epithelium via CCL20 (MIP-3α) production (Figure 1) [19]. CCL20 is the only chemokine known to interact with CCR6 that is expressed by

Interactions of epithelial cells with T cells

Airway epithelial cells induce migration of Th1 cells into mucosae via production of the CXCR3 ligands, CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC), and induce migration of Th2 cells via production of the CCR8 ligand CCL1 (I-309) and the CCR4 ligands CCL17 (TARC) and CCL22 (MDC) (Figure 1) [42, 43, 44, 45, 46, 47]. CXCR3 is expressed on activated T cells, predominantly of the Th1 phenotype, as well as on NK cells and a subset of circulating memory CD4⁺ and CD8⁺ T cells. CXCR3 ligands are

Interactions of epithelial cells with B cells

Mucosal surfaces are continually exposed to potentially harmful substances including microbial pathogens. Local immunoglobulin class switch recombination (CSR) and production of IgA and IgE in the upper airway have been proposed to be important events in both protection from pathogens and the pathogenesis of airway allergic diseases in response to otherwise innocuous antigens. Although CSR is generally thought to be highly dependent on CD40-CD40L ligation, it is also reported that viral and

STAT6-dependent airway inflammation and mucus production

In vivo studies in mice have indicated that allergen- and IL-13-induced airway inflammation are dependent on the activation of signal transducer and activator of transcription 6 (STAT6) in the airway epithelial cells. Although epithelial cells are involved in regulation of recruitment and activation of DC, T cells and B cells (see above) and eosinophils, neutrophils and basophils (not discussed), other important responses of epithelium in immunity and disease are the formation of fibrogenic

Anti-inflammatory effects of epithelium

Epithelial cells play roles in the regulation of inflammation by production of several families of anti-inflammatory molecules, including cytokines (IL-10, TGF-β), soluble cytokine receptors/receptor antagonists (sIL-1RN, sIL-13RA2, sTNFR1), protease inhibitors (SLPI, SERPINA1 (α1-antitrypsin), SERPINB1, TIMP-1), inhibitory arachidonic acid metabolites (PGE2, PGI2, lipoxin A4) and others (CC10, SP-A, etc.). Epithelial cells also express anti-inflammatory or immunosuppressive cell surface

Conclusions

Airway epithelial cells act first as a physical barrier that protects against inhaled substances and pathogens. It is now becoming increasingly clear that airway epithelial cells express PRRs that recognize microbial pathogens and activate innate host defense mechanisms in the airway. Activation of innate immunity in the epithelium secondarily induces recruitment and activation of DC, T cells and B cells that amplify antigen recognition, antibody production and other adaptive immune responses.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This research is supported in part by NIH grants, R01 HL068546, R01 HL078860 and 1R01 AI072570 and by a grant from the Ernest S. Bazley Trust.

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Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

Introduction

Section snippets

Epithelium and innate immune recognition

Epithelium and host defense

Interactions of epithelial cells with DC

Interactions of epithelial cells with T cells

Interactions of epithelial cells with B cells

STAT6-dependent airway inflammation and mucus production

Anti-inflammatory effects of epithelium

Conclusions

References and recommended reading

Acknowledgements

Cell

Proc Natl Acad Sci U S A

J Cell Physiol

Science

Curr Opin Immunol

J Clin Invest

Clin Exp Allergy

Signaling pathways downstream of pattern-recognition receptors and their cross talk

Annu Rev Biochem

Cooperation of Toll-like receptor signals in innate immune defence

Nat Rev Immunol

Activation of airway epithelial cells by toll-like receptor agonists

Am J Respir Cell Mol Biol

Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells

Am J Respir Cell Mol Biol

Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells

J Virol

IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein

Cell Microbiol

Nod-like proteins in immunity, inflammation and disease

Nat Immunol

Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae

J Biol Chem

Dectin-1: a signalling non-TLR pattern-recognition receptor

Nat Rev Immunol

Pneumocystis cell wall beta-glucans stimulate alveolar epithelial cell chemokine generation through nuclear factor-kappaB-dependent mechanisms

Am J Respir Cell Mol Biol

Innate and acquired immunity and epithelial cell function in chronic rhinosinusitis

Clin Allergy Immunol

Role of bacterial superantigens in atopic dermatitis: implications for future therapeutic strategies

Am J Clin Dermatol

An update on the impact of Staphylococcus aureus enterotoxins in chronic sinusitis with nasal polyposis

Rhinology

Allergic airway inflammation inhibits pulmonary antibacterial host defense

J Immunol

Role of deficient type III interferon-lambda production in asthma exacerbations

Nat Med

Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus

J Exp Med

Interactions between airway epithelial cells and dendritic cells: implications for the regulation of airway inflammation

Curr Drug Targets

Many chemokines including CCL20/MIP-3alpha display antimicrobial activity

J Leukoc Biol

Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter

Am J Respir Cell Mol Biol

Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway

J Immunol

Impact of bronchial epithelium on dendritic cell migration and function: modulation by the bacterial motif KpOmpA

J Immunol

Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment

J Allergy Clin Immunol

Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation

J Exp Med

The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis

Am J Respir Crit Care Med

Airway epithelial interleukin-15 transforms monocytes into dendritic cells

Am J Respir Cell Mol Biol

Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP

Nat Immunol

TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

J Exp Med

Thymic stromal lymphopoietin: master switch for allergic inflammation

J Exp Med

TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation

Annu Rev Immunol

A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells

Exp Hematol