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Published ahead of print on January 26, 2006, doi:10.1165/rcmb.2006-0022SF
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 548-551, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2006-0022SF

Airway Epithelium, Inflammation, and Mechanisms of Disease: A Tribute to Carol B. Basbaum

Flagellar Activation of Epithelial Signaling

Alice Prince

College of Physicians & Surgeons, Columbia University, New York, New York

Correspondence and requests for reprints should be addressed to Alice Prince, College of Physicians & Surgeons, Columbia University, 650 W. 168th Street, BB4-416, New York, NY 10032. E-mail: asp7{at}columbia.edu

Abstract

Mucosal epithelial cells are an important component of the innate immune system forming a physical and immunologic barrier to inhaled bacteria. As polarized cells with tight junctions, the immunologic signaling functions of airway epithelial cells differ from those of professional immune cells. While many bacterial gene products activate airway mucosal cells, flagella are especially immunostimulatory. The motility function provided by flagella is essential for the initial stages of respiratory infection associated with opportunists such as Pseudomonas aeruginosa. Apically presented toll-like receptor 5 responds specifically to bacterial flagellin transducing a number of epithelial proinflammatory signaling cascades, including the induction of Ca2+ fluxes; activation of NF-{kappa}B, IL-8, and matrilysin; and mucin expression. The complexities of flagella and flagellin structures, how these bacterial components initiate host signaling and their potential as a vaccine target are reviewed.

The mucosal cells lining the respiratory tract are actively involved in surveillance and signaling functions responding to the potential threat of inhaled bacteria. To accomplish these functions, the airway cells must express receptors that recognize specific bacterial components and must be able to communicate not only with other epithelial cells that form the mucosal barrier, but with the professional immune cells that will direct and regulate the ensuing immune response. Much of the data regarding the immune function of airway epithelial cells is derived from studies of the pathogenesis of Pseudomas aeruginosa infection in cystic fibrosis (CF). CF is characterized by chronic airway infection with P. aeruginosa, opportunistic pathogens which stimulate an intense polymorphonuclear leukocyte (PMN) response that prevents bacterial invasion but eventually results in fibrosis and respiratory failure. Many P. aeruginosa components stimulate innate immune responses (1). Organisms at different stages in the colonization and infection process produce different gene products that trigger epithelial host defenses. One of the most immunostimulatory products of P. aeruginosa, especially the motile, environmental strains thought to initiate infection in CF, are flagella (2). The introduction of therapeutic agents to modulate immune responses, such as the TNF receptor analogs and monoclonal antibodies that thwart leukocyte activation in other inflammatory disorders, could be readily applied to lung inflammation as well. It should be possible to modulate airway inflammation without predisposing the host to invasive bacterial infection. However, to develop such therapies the immunostimulatory bacterial components must be characterized as well as the signaling cascades that are activated.

P. aeruginosa in particular express a number of gene products that are presented on the cell surface or released during active growth that stimulate epithelial or cells of hematopoietic origin (1, 3). The discovery of the toll-like receptors (TLR), the eukaryotic receptors that respond to various "pathogen associated molecular patterns," indicated how the host signals the presence of bacterial products (4): cell wall fragments, peptidoglycan, CpG DNA, LPS, flagella (5) and other components (6). P. aeruginosa products that have received most interest include the adhesins, pili or fimbriae, LPS (historically presumed to be the major immunostimulant), and flagella. However, signaling through the LPS-specific toll-like receptor TLR4 is minimal in airway cells and seems unlikely to account for the florid airway inflammation observed in response to Pseudomonas infection (7). In contrast, flagella, bacterial appendages that provide motility and chemotaxis functions, appear to be the predominant immunostimulant of P. aeruginosa, particularly in the initial stages of pulmonary infection. These flagella are involved in many host–bacterial interactions, as will be reviewed below.

PROPERTIES OF P. aeruginosa FLAGELLA

P. aeruginosa generally express a single polar flagellum, which exhibits the typical, conserved structure established for many gram-negative pathogens (8). These flagella provide motility and chemotaxis functions for the organisms. Detailed genetic analyses of P. aeruginosa flagella performed by Dasgupta and colleagues have provided a large amount of data to explain the biology and regulation of these important virulence factors (9). Most P. aeruginosa isolates express one of two types of flagella (a or b) based on the deduced amino acid sequences of the major structural gene fliC, encoding the flagellin filament (10). At the tip of the flagella is a cap protein, FliD, which also provides some sequence variability (A or B) (11). Several studies have demonstrated that Pseudomonas flagella are variably glycosylated (12), although it is unclear exactly how this affects either their function or immunogenicity (13). Flagellar biosynthesis is controlled at several levels, by FleQ, an NtrC-type {sigma}70–dependent activator similar to the system found in Vibrio cholera, as well as a number of other genes (14). Flagellar genes are expressed in planktonically growing organisms, the motile environmental strains associated with the initial infection of the CF lungs. However, P. aeruginosa isolates from chronically infected patients have been found to exhibit an RpoN mutant phenotype, lacking expression of both flagella and pili (15).

FLAGELLA AND PATHOGENESIS

Studies of the role of flagella in the pathogenesis of acute pneumonia indicated that they were essential to establish infection. In the mouse lung, nonmotile FliC- mutants could cause local inflammation where they were instilled, but failed to disseminate throughout the lung or into the bloodstream (16). Isolated flagella were highly immunostimulatory when instilled directly into the airways, evoking a florid PMN response. Flagella function as ligands for macrophages and facilitate clearance of flagellated bacteria from the airways (17). Flagella also interact with airway mucins, providing a mechanism for clearance from normal airways (18, 19). The molecular basis for the interactions between P. aeruginosa flagella and specific components of the airway host defenses have since been explored by many laboratories.

P. aeruginosa FLAGELLA AND THE AIRWAY EPITHELIUM

The importance of flagella in activating innate immune responses at mucosal surfaces has been analyzed in great detail particularly in the gut (20) but also in the lung (2, 7). One of the highly conserved toll-like receptors, TLR5, was found to be activated specifically by bacterial flagellin (5). The distribution of this receptor is an important mediator of flagellin-induced inflammation. Using alanine-scanning mutagenesis, the TLR5 recognition site was localized to a cluster of 13 amino acids on flagellin, at a site that is important in motility, but buried within the intact flagellin filament (21). Interestingly, this is a region not expected to be modified by post-translational processes, such as glycosylation (12). As flagellin was co-precipitated with TLR5, the ligand and receptor appear to be in physical contact. Exactly how intact flagella are disassembled into flagellins in the airway is unclear. Neutrophil proteases can cleave the flagellins, destroying their immunogenicity (22), and glycosylation may protect sites of potential protease cleavage. While TLR5 is widely expressed in immune cells such as macrophages, dendritic cells, and neutrophils, it is of particular interest to establish its distribution in the airway epithelium, as excessive epithelial immune signaling has been thought to be central to the pathophysiology of lung disease in CF.

TLR5 IN EPITHELIAL CELLS

TLR5 is present in human and murine airway cells (7, 23, 24). Since flagellin must bind directly to TLR5, the receptor must be accessible at the apical surface of the epithelial cell to initiate signaling from organisms within the airway lumen. In CF, the bacterial mass, growing in a biofilm, is thought to be enmeshed in mucus within the airway (25) (Figure 1). Flagellated planktonic organisms that break free from the bacterial community could readily shed flagella within the airway lumen (26). The airway epithelium remains intact in CF. Even in the late stages of the disease (27), bacteria rarely become invasive. Thus flagella–TLR5 interactions must occur predominantly on the apical surface of airway cells, at least in CF. It is possible in other modes of infection, such as more invasive P. aeruginosa infections typical of nosocomially acquired pneumonias (28), that basolaterally displayed receptors are also activated (29). Studies performed with human cells in primary culture as well as transformed cell lines indicate that TLR5 is constitutively displayed on the apical surface and can be readily mobilized to the apical surface in response to ligand (2, 7) (Figure 2). Other investigators suggest that flagellar activation, and hence TLR5, is primarily basolateral, but these conclusions may be limited to the specific properties of the transformed cell line under study (29). Flagella also bind to a number of glycolipids, including asialoGM1. This glycolipid is apically displayed on the surface of airway cells and is concentrated in lipid rafts that contain TLR2 (30). Flagella bound to asialoGM1 can initiate NF-{kappa}B signaling in airway cells through TLR2 in addition to the flagellin receptor TLR5 (1, 2). This situation is distinct from that in the gut, in which TLR5 is basolateral and bacteria must invade to engage TLR5 signaling (20). The apical display of TLR5 in the airway is consistent with its barrier and signaling function and a low threshold for activation in response to perceived pathogens. In contrast, mucosal cells of the gut are continually exposed to bacterial products, and proinflammatory signaling must be restricted to invasive pathogens.


Figure 1
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  		Figure 1. Histopathology of infected cystic fibrosis (CF) airways. A hematoxylin-eosin–stained section of CF lung tissue at the time of lung transplantation is shown. Note that, despite accumulation of polymorphonuclear leukocytes (PMNs), mucin, and bacteria in the airway, the epithelial tight junctions appear intact. Bacteria are enmeshed in mucin not juxtaposed to the airway surface or within cells. (Courtesy of Michael Welsh, University of Iowa. Originally published in Ref. 40.)

 

Figure 2
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  		Figure 2. Distribution and colocalization of asialoGM1, TLR2, TLR5, and flagella in permeabilized human airway epithelial cells. (A) 16HBE cells or (B) human airway cells in primary culture (NHNP), grown at an air–liquid interface, were examined by confocal microscopy (z-secions) 1 h after the addition of Alexa Fluor 594–tagged flagella (red) and treated with either Alexa Fluor 488 (green) labeled asialoGM1, TLR2, or TLR5 (magnification: x100). Areas of colocalization are yellow, indicated by arrows. (C) 16HBE cells after 4 h of exposure to flagella now have apical TLR5 colocalized with the flagella, which remain on the apical surface, as compared with caveolin-1 (Cav-1) control, which is present throughout the cell. (Originally published in Ref. 2.)

 
SIGNALING CASCADES ACTIVATED BY FLAGELLA

Microarray studies comparing the activation of epithelial gene expression by motile versus nonmotile mutants of P. aeruginosa clearly demonstrate the importance of flagella in proinflammatory signaling pathways (31). This is entirely consistent with previous studies that implicated the activation of NF-{kappa}B–dependent genes, especially IL-8, the PMN chemokine, in response to flagella, as well as mucin and matrilysin expression (32). Many of the details of these signaling cascades have been defined. The application of P. aeruginosa flagella to the apical surface of human airway cells in primary culture stimulates a 100 nM Ca2+ flux which is both necessary and sufficient to activate MAPKs, NF-{kappa}B, and IL-8 production (2, 33). The signaling pathway includes activation of Ras, c-Src, and ERK MAPKs, resulting in both IL-6 and IL-8 production. Although it is unclear how Ca2+ transients are linked to distal MAPK and NF-{kappa}B responses, induction of such fluxes are expected effects of TLR5 activation. PI3K and PLC{gamma} have been implicated in the initiation of TLR2 signaling (34), and it is possible that release of Ca2+ from intracellular stores, perhaps from caveolae (30), is directly linked to flagellar TLR2 or TLR5 activation. Flagella-asialoGM1 recognition also activates a TLR-dependent cascade, presumably through the interaction of asialoGM1 and TLR2. TLR2-null mice have diminished inflammatory responses to flagella, indicating some participation of TLR2 as well as TLR5 in flagella signaling (2).

Flagella–asialoGM1 signaling was initially characterized by McNamara and colleagues (35). They demonstrated that flagella–asialoGM1 interactions activated MUC-2 expression. The signaling cascade also involved the activation of Ca2+ fluxes, but was associated with the generation of ATP and activation of purinergic receptors. The notion that bacterial flagella could trigger autocrine nucleotide signaling was especially intriguing. These studies were performed with HEK cells or HME 3 cells, a gut epithelial cell line, transfected with a MUC-2 reporter. In contrast, the flagella–asialoGM1 interaction examined in airway cells leading to TLR-mediated responses does not involve P2Y receptors and was not inhibited by either apyrase or reactive blue (2), suggesting some tissue-specific differences in signaling.

FLAGELLA AND MUCIN

Numerous studies performed over the past two decades have demonstrated the binding of P. aeruginosa flagella to human mucins. As the composition of airway mucins is apparently affected by CF transmembrane conductance regulator dysfunction (36), the enhanced association of the organism and airway secretions has been thought to explain the predilection of P. aeruginosa for the CF airways. Whether there is really differential binding to CF versus normal mucins remains controversial. However, the association of flagella, and specifically the cap protein FliD, with specific components of human mucins (11), such as Lewis X derivatives, is well established (18). Flagella also bind specifically to MUC-1, a cell surface–associated mucin, at least in vitro as overexpressed in Chinese hamster ovary cells (37). Moreover, flagella stimulate the phosphorylation of the MUC-1 cytoplasmic tail activating MAP kinases, although the distal components of this cascade have not been identified (38). While human airway cells express MUC-1 at their apical surfaces (7), the relative affinity of flagella for MUC-1 versus TLR5, asialoGM1, or other receptors is not established.

FLAGELLA-BASED VACCINES

The properties of P. aeruginosa flagella, their relatively conserved structures, antigenicity, and critical role in bacterial virulence have made them attractive candidates for the development of vaccines. The notion that motile, environmental isolates of P. aeruginosa initiate airway infection would support the use of a flagella vaccine in high-risk patients before the onset of chronic infection. Less clear is the utility of such a vaccine in patients already colonized, who likely harbor biofilms of P. aeruginosa that have significantly less flagellar expression. It is difficult in young patients with CF to differentiate the uninfected from those who have lower airway colonization but do not produce sputum. As flagella are highly antigenic, serologic tests could be used to differentiate such patient populations. Such vaccines have been developed and clinical trials are in progress (39).

SUMMARY

In the normal host, the epithelium provides formidable barrier and surveillance functions, clearing inhaled organisms silently and efficiently. When bacteria persist in the airway, as in CF, mucosal epithelial cells are readily stimulated and contribute substantially to the recruitment and activation of professional phagocytic cells. P. aeruginosa flagella are but one of the major bacterial gene products that induce multiple innate immune responses ranging from proinflammatory cytokine, chemokine, and mucin production. The central role of flagella in pathogenesis makes them a very attractive target for strategies to prevent pulmonary infection, particularly in the patients at known risk.

Footnotes

Originally Published in Press as DOI: 10.1165/rcmb.2006-0022SF on January 26, 2006

Conflict of Interest Statement: A.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 19, 2006

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