Immune response - Bacterial infections in normal airways

Bacterial infections in normal airways

The upper airways represent a primary site for the introduction of pathogenic microorganisms from inspired air. The ciliated epithelium features several powerful mechanisms for prevention of colonization by inhaled bacteria, thus the lower respiratory tract usually remains sterile. Toll-like receptors (TLRs) play a key role in facilitating the innate immune response to bacterial antigens [1].

Toll-like receptors (TLRs) belong to a family of transmembrane proteins that can recognize and discriminate a diverse array of microbial antigens. Following their activation by specific bacterial ligands, TLRs initiate intracellular signaling cascades that culminate in the activation of transcription factors and ultimately lead to activation of pro-inflammatory gene expression (acute inflammatory response). Epithelial cells content of the airways provide both a physical barrier to infection and an active defense mechanism against invading microoranisms [2].

TLR2 is the predominant TLR expressed on the apical cell surface, with other TLRs (TLR1, TLR4 and TLR5) residing mainly intracellularly. However, in inflamed lung following stimulation with bacterial ligands TLR5 and TLR4 can be mobilized to the apical surface [2].

All TLRs, as well as IL-1RI, induce the canonical pathway of NF-kB activation which consists of MyD88/ IRAK4 and IRAK1/2/ TRAF6/ TAB1 and TAB2/ TAK1(MAP3K7)/ NIK(MAP3K14)/ IKK (cat)/ I-kB/ NF-kB cascade [2], [3], [4]. TLR2 and TLR4 signaling pathways also require an additional adaptor TIRAP (Mal) [5], [6].

TLR signaling and NF-kB activation are commonly involved in the up-regulation of chemotactic molecules and cytokines (such as Interleukins IL-1 beta, IL-6 and IL-8), production of mediators of innate immune response (IFN-gamma and NO that is synthesized by inducible nitric oxide synthase (iNOS), enhanced expression of antimicrobial peptides (such as Beta-defensin 2). IL-1 beta signaling, in turn, regulates the levels of CFTR [7], [8].

Of all the TLRs, TLR2 in conjunction with TLR1 recognizes the broadest repertoire of ligands, such as Lipoteichoic acid (LTA) and Glycopeptide (peptidoglycan, PGN) from gram positive bacteria followed by NF-kB activation and interleukin production [2], [9], [10]. TLR5 is able to recognize Flagellin (from both gram positive and gram negative bacteria), and also stimulate NF-kB signaling [1], [11], [12].

Pseudomonas aeruginosa has been shown to signal through TLR4/ MD-2/ CD14 complex with its LPS moiety [13], [14]. Although TLR4 is expressed in airway epithelial cells, it does not appear to be prominently involved in signaling of P. aeruginosa presented at the apical surface of airway epithelial cells [1], [2], [15], [16]. The low level of MD-2 expression is also proposed to limit the responses of human airway epithelia to endotoxin stimulation [17].

TLR2 can also mediate Beta-defensin 2 expression via NF-kB activation in response to bacterial antigens in human airway epithelia [18], thus promoting an effective immune response [1].

CFTR is a chloride channel that regulates chloride transport, fluid hydration and mucociliary clearance in the lung, thus preventing the bacterial growth in normal airways [1], [19], [20]. Normal CFTR promotes a rapid expression of FasL(TNFSF6) and FasR(CD95), as well as an apoptotic response to P. aeruginosa infection. Mutant deltaF508 CFTR cells are characterized by inhibited apoptosis and delayed FasL(TNFSF6) and FasR(CD95) expression in response to infection [21].

Bacterial stimulation also leads to FasR(CD95)-dependent NF-kB activation [2], [22]. Rapid release of IL-1 beta (most probably NF-kB-dependent) is enhanced in the presence of functional CFTR, but not deltaF508 CFTR in respiratory epithelial cells [22].

The inducible form of nitric oxide synthase (iNOS) is expressed constitutively in normal human airway epithelium [23]. Both NF-kB and IFN-gamma signaling components are necessary for normal iNOS expression. IFN-gamma activates JAK1 and (JAK2/ STAT1 signaling followed by IRF1 and iNOS expression [24]. Activation of PIAS1 results in reduced IRF1 and iNOS expression in CF, but not healthy, epithelial cells [24].

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References:

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