Toll-like receptors: Applications to dermatologic disease Sammy S.W. Kang, MD, Lynda S. Kauls, MD, Anthony A. Gaspari, MD  Journal of the American Academy of Dermatology  Volume 54, Issue 6, Pages 951-983 (June 2006) DOI: 10.1016/j.jaad.2005.05.004 Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 1 The Toll–interleukin 1 receptor (TIR) motif is conserved among all Toll-like receptors (TLR), interleukin 1 receptors (IL-1R), and adaptor molecules such as myeloid differentiation factor 88 (MyD88), Toll–interleukin 1 receptor domain–containing adaptor–inducing interferon-β/Toll–interleukin 1–containing adaptor molecule-1 (TRIF/TICAM-1), and Toll–interleukin 1 receptor domain–containing adaptor protein (TIRAP). Ig, Immunoglobulin; LRR, leucine-rich repeat, MAL, myeloid differentiation factor 88 adaptor-like protein. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 2 Those pathways that are common to Toll-like receptors (TLR), as well as recently elucidated pathways that demonstrate receptor specificities, are depicted. AP-1, Activator protein-1; Elk-1, ETS domain-containing protein; ERK, extracellular-signal-regulated kinase; IFN-β, interferon-β; IFNR, interferon receptor; IκB, inhibitor of NF-κB; IKK, inhibitor of NF-κB kinase; IRAK, interleukin 1 receptor–associated kinase; IRF, interferon regulatory factor; JAK, janus kinase; JNK, c-Jun-NH2-terminal kinase; MD2, TLR4-associated molecule; MKKs, MAPK (mitogen-activated protein kinase) kinases; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; P, phosphate group; p38, a MAPK; STATs, Signal Transducer and Activator of Transcription proteins; TAK-1, transforming growth factor b-activated kinase-1; TBK1, TANK-binding kinase-1; TIRAP, Toll–interleukin 1 receptor domain–containing adaptor protein; Tollip, Toll-interacting protein; TRAF-6, tumor necrosis factor receptor–associated factor 6; TRIF/TICAM-1, Toll–interleukin receptor domain–containing adaptor–inducing interferon-β/Toll–interleukin 1–containing adaptor molecule-1. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 3 Alternate cytokine production profiles can be produced after stimulation of identical Toll-like receptors due to the alternate downstream signaling mediated by TRIF. A, Excess TNF receptor–associated factor 6 (TRAF-6) blocks the binding of TANK-binding kinase-1 (TBK-1) leading to an increased production of NF-κB, whereas (B) production of IFN-β is produced if TNF receptor–associated factor 6 binding is disrupted. This illustrates the myriad of cellular responses elucidated by a limited repertoire of receptors. IRF-3, interferon regulatory factor 3. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 4 Photoimmunosuppression. UV radiation can up-regulate endogenous Toll-like receptor (TLR) ligands such as HSPs (1, 2). By ligating Toll-like receptors, these stress signals activate the Toll–IL-1 receptor signaling cascade (3, 4), leading to the production of immunosuppressive IL-10 and TNF-α (5). The immunosuppressive cytokine milieu is further supported by the production of IL-10 by regulatory T cells (Treg). KC, keratinocyte; LC, Langerhans cell; LN, lymph node. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 5 Toll-like receptor (TLR) signaling defect in xeroderma pigmentosum. Defective Toll-like receptor 3 signaling may be linked to the vulnerability of XP patients to UV-induced skin cancers. As stress signals cannot properly activate Toll–IL-1 receptor pathways to produce IL-12 (an important antagonist of IL-10), the effects of immunosuppressive cytokines would predominate. Also, the tumoricidal activity of NK cells is likely compromised. APC, antigen-presenting cell; KC, keratinocyte; Treg, regulatory T cell. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 6 Inherited IL-1 receptor–associated kinase (IRAK)-4 deficiency. Mutations of the Irak4 gene result in a truncated form of the protein, which prevents the proper assembly of the Toll receptor complex and activation of crucial signaling molecules. Degradation of inhibitor of NF-κB (IκB) does not occur, and as a result, NF-κB cannot translocate into the nucleus to initiate the transcription of proinflammatory cytokines. IKK, inhibitor of NF-κB kinase; P, phosphate group; Staph, staphylococcus; Strep, streptococcus; TAK-1, transforming growth factor β-activated kinase-1. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions

Fig 7 Toll-like receptor 4 (TLR4) mediates the deleterious effects of lipopolysaccharide (LPS). The C57BL/10ScCr mouse has a chromosomal deletion of the Lps locus and hence completely lacks Toll-like receptor 4 expression. In this animal model that utilizes the C57BL/10ScCr and other transgenic mouse strains expressing increasing amounts of Toll-like receptor 4, the level of Toll-like receptor 4 expression was shown to dictate the animal's response and susceptibility to LPS. Journal of the American Academy of Dermatology 2006 54, 951-983DOI: (10.1016/j.jaad.2005.05.004) Copyright © 2006 American Academy of Dermatology, Inc. Terms and Conditions