Differential Recognition of TLR-Dependent Microbial Ligands in Human Bronchial Epithelial Cells

Abstract

*Bronchial epithelial cells represent the first line of defense against invading airborne pathogens. They are important contributors to innate mucosal immunity and provide a variety of antimicrobial effectors. However, mucosal surfaces are prone to contact with pathogenic, as well as nonpathogenic microbes, and therefore, immune recognition principles have to be tightly controlled to avoid uncontrolled permanent activation. TLRs have been shown to recognize conserved microbial patterns and to mediate inducible activation of innate immunity. Our experiments demonstrate that bronchial epithelial cells express functional TLR1-6 and TLR9 and thus make use of a common principle of professional innate immune cells. Although it was observed that TLR2 ligands dependent on heterodimeric signaling either with TLR1 or TLR6 were functional, other ligands like lipoteichoic acid were not. Additionally, it was found that bronchial epithelial cells could be stimulated only marginally by Gram-positive bacteria bearing known TLR2 ligands while Gram-negative bacteria were easily recognized. This correlated with low expression of TLR2 and the missing expression of the coreceptor CD36. Transgenic expression of both receptors restored responsiveness to the complete set of TLR2 ligands and Staphylococcus aureus. Additional gene-array experiments confirmed hyporesponsiveness to this bacterium while Pseudomonas aeruginosa and respiratory syncytial virus induced common, as well as pathogen-specific, sets of genes. The findings indicate that bronchial epithelium regulates its sensitivity to recognize microbes by managing receptor expression levels. This could serve the special needs of controlled microbial recognition in mucosal compartments.

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

“…However, only limited information is available for the situation in the upper airways. It has been reported that the sensitivity and the activation threshold of TLR in bronchial epithelial cells is indeed regulated [6,[14][15][16], supporting the concept that airway epithelial cells actively restrict pattern recognition principles.…”

“…It has been shown convincingly that epithelial cells at surfaces that regularly or permanently encounter microbes express various TLR and are able to actively sense danger due to infectious agents [4][5][6][7][8]. This has two important implications: First, epithelial cells at non-sterile surfaces have to regulate their TLR sensitivity to avoid continuous threat of inflammation and, second, organ-specific mechanisms of regulating immunity have to exist.…”

“…This has two important implications: First, epithelial cells at non-sterile surfaces have to regulate their TLR sensitivity to avoid continuous threat of inflammation and, second, organ-specific mechanisms of regulating immunity have to exist. The first fact has now been intensively studied and multiple mechanisms including threshold regulation of TLR stimulation [6,10], anatomical sequestration [14,26], inhibitory signaling molecules [27,28], coreceptor modulation [6] and specific signaling pathways [29] have been described. The second hypothesis was the subject of this study.…”

“…1A). BEAS-2B cells [6] as well as monocytes both express TLR-4; however, only monocytes respond with induction of TNF-a. We observed that BEAS-2B cells starting from a 1:10 ratio (BEAS-2B:monocytes) inhibited LPS-induced TNF-a secretion from monocytes.…”

“…Nowadays it is known that prototypical pattern recognition receptors including Toll-like receptors (TLR) are not only expressed on professional innate immune cells but also cover epithelial cells within various organs including the gut [4], the airways [2,5,6], the oral cavity [7] and the skin [8]. In addition, it is now clear that TLR not only sense microbial components derived from pathogenic microbes but also recognize microbial compounds in general [9].…”