Members of the TLR Family Expressed by Keratinocytes

Since Gram-positive skin-infecting bacteria such as Staphylococcus aureus (S. aureus) or Borrelia burgdorferi (B. burgdorferi) are known to be rich sources of LTA and lipoproteins, which are well-known ligands of TLR2 homodi-mers (Table 13.1), the abundant and constitutive expression of TLR2 in the epidermis is not surprising [36, 49, 59]. TLR2 homodimers are also involved in the recognition of lipoarabino-mannan of mycobacteria and atypical lipopoly-saccharides of Leptospira and Porphyromonas species [68]. TLR2 also forms heterodimer complexes with other members of the TLR family, namely with TLR1 and TLR6 [49]. These complexes are characterized by different ligand specificity, thus recognition of microorganisms through different complexes gives specificity to the immune response. The TLR2/TLR6 heterodimer is necessary for the recognition of dia-cyl lipopeptide, a common cell wall compound of all Gram-positive bacteria, but it is also involved in the recognition of PAMPs of fungal pathogens (Table 13.1). In contrast, TLR2/TLR1 heterodimers recognize tripalmitoylated lipo-peptides (Table 13.1) [76].

TLR3 has recently been demonstrated to provide a mechanism by which dsRNA species activate the innate immune response (Table 13.1). Signaling through TLR3 leads to the expression of high levels of interferon-gamma-(IFNy) and type-1-(Th1-) associated chemokines in a variety of cell types, suggesting that it has a key role in innate immune responses against viral infections [70].

IL-1R1

IL-1R1

Fig. 13.1. Signal transduction pathways via TLR/IL1R. The TLR signaling pathway is highly homologous to that of the IL-1R family. After binding of an appropriate ligand, both TLRs and IL-1R interact with an adaptor protein, MyD88, through their TIR (Toll/IL-1R) domains. Upon signaling, MyD88 recruits a serine/ threonine kinase, IRAK. IRAK is activated by phos-phorylation and then associates with TRAF6, another adaptor protein, leading to activation of either the JNK pathway, through MAP kinase, or the NF-kB path-

way, through the IKK complex. Signal transduction via TLRs and/or IL1Rs leads to the expression of antimicrobial and antiviral peptides, cytokines and chemokines. [IKK IkB kinase kinase, IRAK IL-1R-asssociated kinase, JNK c-Jun N-terminal kinase, MyD88 myeloid differentiation primary-response protein, NF-kB nuclear factor kappa B, TAK1 growth factor-|3-activated kinase 1, TIRAP TIR- (TLR-IL1-R1-) associated protein, TNF tumor necrosis factor, TRAF6 TNF-receptor-associated factor, TRIF Toll-receptor-associated activator of interferon]

Fig. 13.1. Signal transduction pathways via TLR/IL1R. The TLR signaling pathway is highly homologous to that of the IL-1R family. After binding of an appropriate ligand, both TLRs and IL-1R interact with an adaptor protein, MyD88, through their TIR (Toll/IL-1R) domains. Upon signaling, MyD88 recruits a serine/ threonine kinase, IRAK. IRAK is activated by phos-phorylation and then associates with TRAF6, another adaptor protein, leading to activation of either the JNK pathway, through MAP kinase, or the NF-kB path-

way, through the IKK complex. Signal transduction via TLRs and/or IL1Rs leads to the expression of antimicrobial and antiviral peptides, cytokines and chemokines. [IKK IkB kinase kinase, IRAK IL-1R-asssociated kinase, JNK c-Jun N-terminal kinase, MyD88 myeloid differentiation primary-response protein, NF-kB nuclear factor kappa B, TAK1 growth factor-|3-activated kinase 1, TIRAP TIR- (TLR-IL1-R1-) associated protein, TNF tumor necrosis factor, TRAF6 TNF-receptor-associated factor, TRIF Toll-receptor-associated activator of interferon]

The expression level of TLR4 by keratino-cytes depends on the anatomical location [49]. Moreover, the expression of TLR4 (together with that of TLR2) correlates with the state of differentiation of keratinocytes [60]. Interestingly, the level of expression may also show inter-individual differences or may be inducible by mechanical injury or inflammation [59]. The recognition of Gram-negative bacteria-derived LPS requires at least two cofactor proteins in addition to TLR4. During LPS signaling, LPS

first binds to CD14, which then interacts with TLR4 and initiates intracellular signal trans-duction. MD-2 is a protein that associates with the extracellular domain of TLR4 and enhances LPS responsiveness (Table 13.1, Fig. 13.1) [65].

TLR5 recognizes the bacterial motor protein flagellin (Table 13.1) required for the motility of microorganisms such as B. burgdorferi, which causes migratory erythema during the course of Lyme disease, and Salmonella typhi, which causes cutaneous ulceration [46]. Keratinocytes

are able to upregulate their chemokine expression in response to B. burgdorferi, indicating that TLR5 is functional on keratinocytes and enables them to respond to invading flagellated bacteria [16].

TLR9 senses unmethylated bacterial CpG DNA derived from many classes of bacteria during infection (Table 13.1). Its expression in the epidermis is inducible by either microbial compounds or physical trauma [12, 45]. Unlike TLR1-TLR6, TLR9 is not expressed on the cell surface but in the endoplasmic reticulum [2].

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