The human skin is densely populated with resident microbiota, composed of commensal microorganisms such as S. epidermidis, P. acnes, Micrococcus luteus and/or Malassezia furfur. These microorganisms compete for nutrients and space, limiting each other's population size and also competing out pathogens that may attempt to colonize the skin. Despite the density of the microbiota, epidermal keratinocytes do not activate pro-inflammatory signaling cascades in response to commensal microorganisms, suggesting a complex host-microbe relationship in the epidermis. Thus, epidermal keratinocytes may need to discriminate the presence of commensals from the presence of pathogens, by mechanism/s that are not yet fully identified One possible explanation for the un-responsiveness of the skin to resident microbiota is the anatomical localization of the TLR-ex-pressing keratinocytes. Since TLRs are expressed by the basal keratinocytes, the layer that is normally not exposed to commensal microorganisms living on the surface of the skin, the sterile and PAMP-free anatomical site may allow the constitutive expression of functional TLR complexes by keratinocytes. These cells initiate pro-inflammatory signaling only during destructive or invasive infection, breaching through the stratum corneum. Still, limitation of TLR expression to certain protected anatomical sites may not be the whole explanation, since TLRs are also expressed in the suprabasal layers of the epidermis [4, 36, 59].
Another explanation may be the induction of tolerance, a state of acquired functional unre sponsiveness in keratinocytes that has been extensively studied in macrophages by the long-term presence of commensal bacteria. That commensals modulate TLR signaling is best shown by studies indicating that signaling through TLR4 or TLR2 in epithelial cells in vitro readily occurs after initial exposure to PAMPs, but not after second exposure or prolonged incubation with TLR agonists. This downregulation of signaling may occur by decreased TLR expression on the cell surface, as well as by the inhibition of TLR signaling via the expression of a non-signaling truncated form of MyD88 or by the activation of IRAK-M, a negative regulatory member of the IRAK family [18, 58, 67]. Alternatively, members of the resident flora may provide an inhibitory signal for kera-tinocytes to avoid inflammation in healthy individuals. However, the molecular mechanisms involved in the induction of tolerance are not entirely understood in keratinocytes and a deeper insight into these processes will most probably change our understanding of the intimate relationship between epidermal cells and the commensal microbiota.
The expression of different PRRs allows keratinocytes to identify numerous features of a single microbe simultaneously. In the presence of functional receptors, effective immune response occurs only upon recognition of specific antigen combinations. Blocking of TLR2 and/or TLR4 suppresses keratinocyte activation induced by P. acnes or Mycobacterium tuberculosis, emphasizing the role of the cooperation between different subfamilies of TLRs in the process of discrimination between commensals and pathogens [54, 61]. The "teamwork" involving TLR subfamilies enables keratinocytes to give pathogen-specific immune responses, or, in the case of skin-resident microorganisms, tolerance.
Skin commensals (e.g., S. epidermidis and P. acnes) and pathogenic bacteria both induce the expression of hBD-2 in primary keratino-cytes. Still, NF-kB transcription factor is not involved in the induction by commensals, suggesting the presence of discrete signaling pathways that enable keratinocytes to discriminate between resident and pathogenic microorganisms. The in vivo biological significance of com
mensal-induced TLR signaling is the induction of cytoprotective factors in epithelial cells. The lack of TLR-MyD88 signaling in mucosal epithelial cells (and most probably in keratino-cytes) is accompanied by decreased capacity of the cells to produce cytoprotective factors such as IL-6 . In the absence of these compounds, epithelial cells are highly sensitive to physical stress-induced cell death. Thus, activation of TLRs by commensal microbiota is probably critical for the protection against physical-injury-associated cell death through the induction of cell survival and/or repair during infection.
Finally, the correlation of follicular lipids with P. acnes in acne vulgaris, an inflammatory but not infectious disease, may indicate a new and unexpected role of skin commensal microorganisms, such as P. acnes and S. epidermidis, on human skin. Their presence may be skin protective and required for a permanent, low activation level of innate immunity in order to defend skin from acute attacks by pathogens, supporting the hypothesis of a genuine inflammatory etiology for acne and a possible, delayed, contribution by P. acnes [22, 54].
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