Copyright #ERSJournals Ltd 2004 EurRespir J 2004;23: 327– 333 EuropeanRespiratory Journal DOI: 10.1183/09031936.03.00098803 ISSN0903-1936 Printedin UK –allrights reserved REVIEW Innateimmunity in the lung: how epithelialcells ght against respiratorypathogens R. Bals*,P.S. Hiemstra # Innateimmunity in the lung: how epithelial cells ® ghtagainst respiratory pathogens *Deptof Internal Medicine, Division of R Bals, P S Hiemstra #ERS JournalsLtd 2004 PulmonaryMedicine, Hospital of the Uni- versityof Marburg, Philipps-University, ABSTRACT: Thehuman lung is exposed to a largenumber of airborne pathogens as a # resultof the daily inhalation of 10,000 litres of air Theobservation that respiratory Marburg,Germany; Deptof Pulmonology, LeidenUniversity Medical Center, Leiden, infectionsare nevertheless rare is testimony to the presence of anef®cient host defence TheNetherlands systemat the mucosal surface of the lung Theairway epithelium is strategically positioned at the interface with the Correspondence:P S Hiemstra,Dept of environment,and thus plays a keyrole in this host defence system Recognition Pulmonology,Leiden University Medical systemsemployed by airwayepithelial cells to respond to microbialexposure include the Center, P O Box9600, 2300 RC Leiden, The actionof the toll-like receptors Netherlands Theairway epithelium responds to such exposure by increasing its production of Fax:31 715266927 mediatorssuch as cytokines, chemokines and antimicrobial peptides Recent® ndings E-mail: p s hiemstra@lumc nl indicatethe importance of these peptides as effector molecules of innate immunity by Keywords:Innate immunity, defensins, cathe- killingmicroorganisms, but also as regulators of in¯ ammation, immunity and wound licidins,infections, epithelium, antimicrobial repair Finally,the clinical relevance of thefunctions of theairway epithelium in innate peptide immunityis discussed EurRespir J 2004;23: 327± 333 Received:August 29 2003 Accepted:October 16 2003 Thestudies were supported by grants from: DeutscheForschungsgemeinschaft the Bun- desministeriumfu ÈrBildungund Forschung, andthe Cystic ® brosis foundation,Dutch Asthmafoundation and Netherlands Organi- zationfor Scienti®c Researchand the EuropeanRespiratory Society The integrity of the respiratory tract critically depends on a whichcytokines and other mediators secreted from the airway tightly regulated host defence apparatus The innate immune epithelium are likelyto playa critical role [3] The role of system provides initialprotection against microorganisms antimicrobialpeptides, smallendogenous antibiotics with and stimulates the adaptive immuneresponse [1] Cellular proin¯ammatory, and other functions, is less clear components ofthe innate immunesystem include phagocytes The aimof this review is to highlightthe role of the airway such as neutrophils or macrophages, natural killercells, epitheliumin host defence and to describe new developments basophils,mast cells, eosinophils and others Epitheliaof the inthis rapidlyevolving area of research Both the recognition humanbody form interfaces between the internal milieuand systems used byairwayepithelial cells to © sense the microbial the external environment In the respiratory tract, the world’ and the effector molecules produced inbasal condi- epitheliallining the airways is the ®rst point of contact for tions and inresponse to microbialexposure are described inhaledsubstances such as environmental pollutants, cigarette The focus inthis latter part is on antimicrobialpeptides smoke, airborne allergens, and microorganisms [2] In recent Whereas this review is mainlydevoted to airwayepithelial years it has become clear that airwayepithelial cells not only cells, also research on other epithelia (mainlythose of the skin provide apassive barrier function, but also actively contribute and the intestine) that is relevant to pulmonaryresearch is to the innate immunesystem [2,3] discussed Important input to the content of this review came The innate immunefunctions of airwayepithelial cells are from the European Respiratory Society research seminar of signi®cance for the pathogenesis of avariety of human "Host defence function of the airwayepithelium " that was diseases Failureof the localhost defence apparatus may held inNoordwijkerhout, The Netherlands, 7± 8November, result inmicrobialcolonisation and subsequently infection of 2002 the airways and the lungparenchyma Mechanisms of the basal immunityprovided by airwayepithelial cells have a critical role inthese settings Activities of the innate immune Recognitionof pathogensby airway epithelial cells system are closely linkedto in¯ammatory processes All majordiseases of the lunginvolve mechanisms of the innate The airwayepithelium senses bacterial exposure and or adaptive immunesystem Asthma and chronic obstructive responds accordingly byincreasing its defences Thisresponse lungdisease (COPD)are chronic in¯ammatory diseases, in consists of an increase inthe release of e g antimicrobial 328 R BALS peptides into the lumenof the airways,and the release of Table 1. –Pattern recognition receptorsinvolved in the chemokines and cytokines into the submucosa that initiate an recognition of microorganismsby airway epithelial cells in¯ammatory reaction Thisin¯ ammatory reaction includes the recruitment of phagocytes, that serve to remove micro- Receptor Ligand organisms that are not cleared by the epitheliumitself, and dendritic cells and lymphocytes that mayaid to mount an TLR1 Tri-acyllipopeptides adaptive immuneresponse TLR2 Lipoteichoicacid, peptidoglycan, zymosan, Mechanisms to recognise pathogens by the airwayepithe- microbiallipoproteins and lipopeptides, liumare therefore considered essential to mount aprotective HSP70 (host) response ofthe innate immunesystem It has been knownfor TLR3 double-strandedRNA TLR4 LPS,HSP60 and70 (host),hyaluronic acid alongtime that cells can respond to microbialproducts such fragments (host) as lipopolysaccharide and lipoteichoic acid However, the TLR5 ¯ agellin exact mechanisms and molecules involvedin this response TLR6 di-acyllipopeptides were incompletely understood In the last decade much has TLR7 syntheticcompounds been learnt about the mechanisms that mediate this © adaptive’ TLR8 arm of the innate immunesystem Cellsof the innate immune TLR9 CpG DNA system, includingphagocytes, dendritic cells and epithelial TLR10 cells, use so-called pattern recognition molecules to bindto CD14 LPS conserved molecular patterns that are present on microorganisms CFTR LPS Pattern-recognition molecules can be present insecretions and the circulation insoluble form, such as mannan-binding TLR:Toll-like receptor; HSP: heat shock protein; CpG: bacterial lectin (MBL), or they can be transmembrane molecules that deoxyribonucleicacid (DNA) containing unmethylated CpG dinulceo- tides;LPS; lipopolysaccharide; CFTR: cystic ® brosis transmembrane mediate direct cellular responses to microbialexposure The conductanceregulator; Refer to text and references 5± 8; TLR10 toll-likereceptors (TLR)constitute anintensely studied family expression:R Bals,unpublished observation of pattern recognition receptors (10 members of the human familyhave been recognised to date) that are represented detects certain structural variants of LPSsuch as leptospiral by various members inalmost allcells of the body Their LPS [15] The function of TLR3was revealed by studies of expression has been intensely studied on dendritic cells, and it TLR3knockout mice,showing that TLR3is essential inthe is nowrecognised that these, TLRs,help to shape the response to double stranded (ds) ribonucleic acid (RNA)that adaptive immuneresponse by directing the waythat dendritic is produced during viralinfections [16] TLR3has been cells instruct T-cells Airwayepithelial cells also express a implicatedin the response of epithelialcells to e g rhino- variety of TLRsthat mayhelp them to mount an adequate virus, rhinovirus dsRNAand synthetic dsRNA(polyinosinic- response to microbialexposure Activation of TLRon epithe- polycytidylicacid; poly(I;C)) Thisresponse consists of an lialcells has nowbeen shown to be involvedin the regulation increased expression not onlyof chemokines [6,17], but also of expression of avariety of genes, includingthose encoding of the human b-defensins (hBD)-2 and -3 [6] TLR9mediates cytokines, chemokines and antimicrobialpeptides the response to bacterial deoxyribonucleic acid (DNA) A Followingthe identi® cation oftollreceptors inDrosophila recent study showed that TLR9mediates the response of ¯ies as receptors involvedin the ¯y ’sresponse to microbial exposure [4],the search for mammalianhomologs led to the colonic epithelialcell lines to bacterial DNA,resulting in discovery of TLRin mammals Avariety of bacterial, fungal expression of interleukin (IL)-8 [18] and viralproducts have nowbeen identi® ed as ligandsfor It is important to note that TLRsmay also mediate the various TLRsand other pattern recognition receptors response to endogenous ligands These ligandsinclude heat- expressed by airwayepithelial cells (summarised intable 1) shock proteins and extracellular matrix components, such as Amongthe members of the TLRfamily, TLR4 has been most fragments of hyaluronic acid that are generated during intensively studied and its role inthe response to lipopoly- in¯ammation Alsoeffector molecules of the innate immune saccharide (LPS) has been subject of alarge number of system mayserve as ligandsfor TLRs The collectin sur- studies Studies inLPS-hyporesponsive mice were essential in factant protein A(SP-A)