In addition to being a physical barrier, the skin is an immunological barrier63
. The skin immune response is vital in wounding and infection and also modulates the commensal microbiota that colonizes the skin. Keratinocytes continuously sample the microbiota colonizing the skin surface through pattern recognition receptors
(PRRs), such as Toll-like receptors (TLRs), mannose receptors and the NOD-like receptors. These receptors recognize pathogen-associated molecular patterns
(PAMPs) including flagellin and nucleic acids, as well as lipopolysaccharide from Gram-negative bacteria, mannan and zymosin from fungal cell walls, and peptidoglycan and lipoteichoic acid from Gram-positive bacteria. The activation of keratinocyte PRRs by PAMPs immediately initiates the innate immune response, resulting in the secretion of antimicrobial peptides (AMPs), cytokines and chemokines. Beyond effecting an adaptive immune response, AMPs also directly kill bacteria, fungi and enveloped viruses64
. Therefore, there is a constant interplay among keratinocytes, immune cells and microorganisms that is modulated by AMPs, cytokines, chemokines and microbial peptides.
Despite being constantly exposed to large numbers of microorganisms, the skin can discriminate between harmless commensal microorganisms and harmful pathogenic microorganisms. The mechanism of this discrimination is not fully clear, but may involve the induction of immune tolerance; TLRs may be desensitized by prolonged exposure to commensal microorganisms, either through decreased TLR expression on the cell surface or by activation of the TLR pathway inhibitors interleukin-1 receptor-associated kinase 3 (IRAK3; also known as IRAK-M) and suppressor of cytokine signalling 1 (SOCS1)65,66
. Specificity may also be achieved by combined recognition of PAMPs by PRRs.
, a commensal bacterium, has recently been demonstrated to modulate the host innate immune response. Phenol-soluble modulins produced by S. epidermidis
can selectively inhibit skin pathogens, such as S. aureus
and Group A Streptococcus
, and can even co-operate with host AMPs to enhance killing67,68
. Recent studies demonstrate that commensal-induced TLR signalling may be necessary for cell survival and repair during infection. Lipoteichoic acid produced by S. epidermidis
can inhibit skin inflammation through a TLR2- and TLR3-mediated crosstalk mechanism69
. In addition, S. epidermidis
triggers keratinocyte expression of AMPs through a TLR2-dependent mechanism70
. This body of work definitively links commensal skin microorganisms with modulation of the innate immune response.
Dysregulation of the skin immune response is apparent in several skin disorders (for example, psoriasis, atopic dermatitis
(AD; commonly known as eczema and contact dermatitis), but how dysregulation affects and/or results from changes in the microbiota remains unclear. AD lesions are characterized by low levels of AMP production as compared with levels from normal skin. This is in sharp contrast to psoriatic lesions, which produce abundant quantities of AMPs and are characterized by an activated innate immune response71–75
. AD lesions are also regularly infected with pathogens, especially S. aureus
, and respond to antimicrobial treatment. Upregulation of T helper 2 cytokines in AD lesional skin is likely to partially account for the apparent suppression of the innate immune response that is observed in AD71,72
. There is no clear microbial component to the common form of psoriasis, although the guttate subset of psoriasis has been associated with streptococcal infections76