The skin is a complex organ that carries out numerous functions contributing to its barrier immunity function. Antimicrobial peptides and lipids are secreted onto the cell surface to control bacterial growth. These include dermcidin, which is secreted in human sweat and has broad antimicrobial activity against a range of pathogenic bacteria. Its antimicrobial activity is not affected by the low pH value and high salt concentrations of human sweat [18]. Sebum is made by sebaceous glands found independently of or near hair follicles. Within the sebum are antimicrobial lipids, such as lauric acid and sapienic acid, which play an important role in controlling pathogenic organisms [19].

However, the skin is not a sterile site, and there is extensive research showing the role that the skin microbiota plays in immunity by restricting the growth of pathogenic bacteria [20]. Commensal bacteria have been shown to produce an antimicrobial peptide that synergizes with the human antimicrobial peptide LL37, which together kill the pathogenic bacterium Staphylococcus aureus [21]. However, insult and pathogens are mostly controlled and prevented entry due to structure and barrier immunity in the skin. Skin-resident stromal cells Keratinocytes are the main component of the epidermis. They express Toll-like receptors (TLRs), which are crucial pathogen pattern recognition receptors that when triggered lead to the production of inflammatory cytokines and initiation of an immune response [22]. Keratinocytes have been shown to constitutively express TLR1, -2, -3, -5, -6 and -10 [23,24]. They also have the ability to sense wound damage and produce inflammatory cytokines and chemokines such as interleukin-1b (IL-1b), IL-8 and CCL20 to recruit leucocytes to the site of damage [25].

Keratinocytes express a raft of antimicrobial peptides that control bacterial growth, including adrenomedullin and b-defensins [26,27]. Defensin-1 is constitutively expressed by human keratinocytes and b-defensin-2 and -4 are up-regulated upon inflammatory challenge [2-29]. Keratinocytes can express the antimicrobial peptide Cathelicidin upon stimulation and can store Cathelicidin in cytoplasmic granules until needed [30,31]. Keratinocytes also constitutively express RNase [23], which is a very potent antimicrobial ribonuclease, and upon inflammatory or bacterial challenge there is further increased expression [32]. More recently, it has been proposed that keratinocytes have the ability to process and present antigen to CD4+ and CD8+ T cells, initiating an adaptive immune response [33]. In addition, keratinocytes are the key site for the first step in the vitamin D metabolism pathway, when pro-vitamin D3 (7-dehydro-cholesterol) is metabolized into vitamin D3, catalyzed by UVB. Vitamin D is an important component of a functioning immune system and its metabolism at the skin site contributes to barrier immunity [34].

Dermal fibroblasts are the structural cells of the dermis; their primary function is to secrete extracellular matrix components such as pro-collagen. Fibroblasts express the full range of TLRs, at a higher level than keratinocytes, demonstrating their important role in the detection of pathogens [35]. In vitro studies have shown that dermal fibroblasts can have differing roles in immunity, indeed TLR4 signalling results in the production of inflammatory cytokines such as IL-6, IL-8 and the monocyte chemo-attractant CCL2 [36]. Conversely fibroblasts have been shown to suppress T-cell proliferation via indoleamine 2,3-dioxygenase production, and to skew the T cells to produce immunoregulatory cytokines such as IL-10 [37]. The subcutaneous layer of the skin is predominantly composed of adipocytes – their primary function is to be a repository of energy that responds to hypothermia by producing heat. More recent work has identified the important role of adipocytes in barrier immunity as a significant source of antimicrobial peptides. In response to infection, for example with S. aureus, dermal fibroblasts can differentiate into adipocytes and produce the antimicrobial peptide cathelicidin [38].

Skin-resident immune cells mononuclear phagocytes within the epidermis there is a population of mononuclear phagocytes called Langerhans cells (LCs). These were believed to have been seeded at birth and maintained by local turnover to ensure a steady-state population [39]. However, a recent study demonstrated, in a murine model of immune injury, that repopulation of LCs from peripheral monocytes makes up for the slow repopulation from mature LCs [40]. Langerhans cells are located at the interface with the external environment and as such are multifunctional sentinels of the epidermis. They sample the environment by extension and retraction of their dendrites between the keratinocytes in an amoeba-like movement [41]. They present antigen to T cells within the epidermis to initiate a local immune response and also have the capacity to migrate to the lymph node and initiate immune responses [42]. Within the dermis, there is a more diverse population of mononuclear phagocytes including dermal dendritic cells (DCs) and dermal macrophage populations. Dendritic cells are the sentinels of the immune system, they sample the microenvironment and either present antigen to the resident T cells or migrate through the lymphatics to the lymph node to initiate an immune response [43]. Historical assessment of dermal DCs identified that they are more activated than their blood counterparts; dermal DCs had increased expression of co-stimulatory receptors and were strong stimulators of T-cell proliferation relative to their peripheral blood counterparts [44]. Two main populations of dermal myeloid DCs have been identified; the CD1c+ DCs and the CD141+ DCs. CD141+ DCs are the cells responsible for cross-presenting antigens to CD8+ T cells and have homology to the mouse CD103+ DCs [45]. Very few plasmacytoid DCs are observed in steady-state skin [46].

Macrophages are another type of antigen-presenting cell resident in the dermis and they sense pathogens and damage and initiate an appropriate immune response. In addition to the immune function, macrophages maintain tissue homeostasis through increasing appropriate anti-inflammatory mechanisms, contribute to wound healing, and heal nerves upon tissue injury [47,48]. Macrophages are thought to populate tissues early on but studies have also shown that they are replenished by circulating monocytes [49]. These data are supported by a study in humans showing that CD14+ cells were a transient population of monocyte-derived macrophages [50]. CD163 has been proposed to be a good marker for dermal macrophages, as it specifically identifies skin-specific macrophages that are not recently migrated monocytes [51]. Analysis of the location of these different mononuclear phagocyte populations in the dermis have shown that DCs can be found closer to the epidermis (around 0–20 μm beneath the dermo–epidermal junction) and macrophages are located deeper in the skin (around 40–60 μm beneath the dermo–epidermal junction) [52].