Keratinocyte Derived Effector Molecules in the Innate Immune System of the Skin

sociates with tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), leading to the activation of at least two distinct signaling pathways, JNK and NF-kB. TLR signaling through MyD88 leads to the phosphorylation and degradation of IkB, the regulator protein of NF-kB, an event allowing the nuclear translocation of NF-kB (Fig. 13.1). In the nucleus NF-kB binds to the promoter region of genes of proin-flammatory cytokines/chemokines, antimicrobial peptides, inducible enzymes, and adhesion molecules, which are important effectors or mediators of innate and adaptive immune responses [50, 81].

In keratinocytes, various microbial compounds induce a rapid TLR-dependent intracellular Ca2+ response. In addition, keratinocytes respond to the challenge with S. aureus or Candida albicans (C. albicans) with TLR2-MyD88-NF-kB-dependent induction of inducible nitric oxide synthase (iNOS), supporting the key role of the TLR-MyD88-NF-kB pathway in innate immune functions of the skin [49, 59].

In addition to their common activation of the MyD88-IRAK-TRAF pathway, individual TLRs may activate different, alternative, signaling pathways. These MyD88-independent pathways involve the activation of interferon-regulatory factor-3 (IRF-3) and are utilized by several TLRs such as TLR3 and TLR4/4 (Fig. 13.1). TLR signaling pathways are therefore not identical and the specificity of some pathways may determine the pattern of gene expression, which accounts for the distinguishable biologic responses observed following the activation of specific TLRs by different classes of pathogens [69]. These specific responses may be particularly important in the epidermis, which is constantly colonized by numerous microorganisms that do not induce immune response.

Human skin is exposed to a wide variety of pathogenic microorganisms. Despite these mi-crobial threats, skin is highly resistant against infections. TLR-mediated signaling upon challenge with microbes and/or microbial-derived compounds induces a chemical cutaneous defense system based on the production of antimicrobial peptides and pro-inflammatory cyto-kines/chemokines. These keratinocyte-derived soluble factors are fundamental in the elimination of invaders and recruitment of T cells and neutrophils into the sites of skin infection.

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