Toll-like receptors: role in dermatological disease

Abstract

Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics.

Figure 1

(a) Cross-section of epidermis. Keratinocytes are present throughout the skin; other epidermal cell types include Langerhans cells, melanocytes, and merkel cells. (b) Keratinocytes express TLRs 1, 2, 3, 4, 5, 9, and 10. MD2: TLR4-associated molecule; MyD88: myeloid differentiation factor 88; NF-κB: nuclear factor-κB; TRAF-6: TNF receptor-associated factor-6; TRIF: TIR domain-containing adapter protein that induces IFN-β. (c) Langerhans cells express high levels of TLRs 2, 3, 4, 8, and 10. but express low levels of TLRs 1, 5, 6, 7, and 9. (d) Upon activation, myeloid-derived dendritic cells and to a lesser extent keratinocytes release IFNα and IL-18 which stimulate Langerhans cell maturation. With antigen stimulation the Langerhans cell induces a Th1 response. (e) In response to TLRs 2, 3, 4, 7, and 9 melanocytes initiate proinflammatory events via the illustrated pathways.

Figure 1

(a) Cross-section of epidermis. Keratinocytes are present throughout the skin; other epidermal cell types include Langerhans cells, melanocytes, and merkel cells. (b) Keratinocytes express TLRs 1, 2, 3, 4, 5, 9, and 10. MD2: TLR4-associated molecule; MyD88: myeloid differentiation factor 88; NF-κB: nuclear factor-κB; TRAF-6: TNF receptor-associated factor-6; TRIF: TIR domain-containing adapter protein that induces IFN-β. (c) Langerhans cells express high levels of TLRs 2, 3, 4, 8, and 10. but express low levels of TLRs 1, 5, 6, 7, and 9. (d) Upon activation, myeloid-derived dendritic cells and to a lesser extent keratinocytes release IFNα and IL-18 which stimulate Langerhans cell maturation. With antigen stimulation the Langerhans cell induces a Th1 response. (e) In response to TLRs 2, 3, 4, 7, and 9 melanocytes initiate proinflammatory events via the illustrated pathways.

Figure 1

(a) Cross-section of epidermis. Keratinocytes are present throughout the skin; other epidermal cell types include Langerhans cells, melanocytes, and merkel cells. (b) Keratinocytes express TLRs 1, 2, 3, 4, 5, 9, and 10. MD2: TLR4-associated molecule; MyD88: myeloid differentiation factor 88; NF-κB: nuclear factor-κB; TRAF-6: TNF receptor-associated factor-6; TRIF: TIR domain-containing adapter protein that induces IFN-β. (c) Langerhans cells express high levels of TLRs 2, 3, 4, 8, and 10. but express low levels of TLRs 1, 5, 6, 7, and 9. (d) Upon activation, myeloid-derived dendritic cells and to a lesser extent keratinocytes release IFNα and IL-18 which stimulate Langerhans cell maturation. With antigen stimulation the Langerhans cell induces a Th1 response. (e) In response to TLRs 2, 3, 4, 7, and 9 melanocytes initiate proinflammatory events via the illustrated pathways.