The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis

Abstract

As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.

Figure 1

MyD88-dependent and TRIF-dependent TLR signaling pathways. Ligand binding of TLRs by their respective ligands induces dimerization of TLRs and initiates MyD88-dependent or TRIF-dependent signaling cascades. The presence of coreceptors, such as CD14 for TLR2, TLR3, TLR4, TLR7, and TLR9, CD36 for TLR2 and TLR6, and CD44 for TLR4, promotes ligand binding efficiency to TLRs. MD2 is a receptor component associated with TLR4 and enables TLR4 to respond to LPS. Activation of TLR1-TLR2 by the lipopeptide Pam3CSK, TLR2-TLR6 by the lipopeptide Malp2, TLR5 by flagellin, or TLR4 by LPS recruits MyD88 through the adaptor molecule TIRAP. MyD88 then recruits and activates the IRAK complex, which in turn activates TRAF6, which serves as a platform to recruit and activate TAK1 in cooperation with TAB1-3. Once activated, TAK1 activates the IKK-NFκB pathway and the MAPK- (including P38, ERK1/2, and JNK) AP1 pathway. Activated NFκB or AP1 translocates to the nucleus, driving the transcription of genes encoding proinflammatory cytokines, antimicrobial peptides, and costimulatory molecules. Activation of endosomal TLR7 by ssRNA or guanosine, TLR8 by ssRNA, or TLR9 by CpG-DNA not only initiates the MyD88-TRAF6-dependent activation of AP1 and NFκB but also triggers the IRAK-, TRAF6-, TRAF3-, and IKKα-dependent activation of IRF7, translocation of which induces the transcription of type1 interferon genes including IFNα and IFNβ. In contrast, activation of TLR3 by dsRNA initiates the TRIF-dependent pathway, whereas TLR4 activation induces both MyD88- and TRIF-dependent pathways. Once recruited to the intracellular domain of TLRs by TRAM, TRIF initiates a TRAF3-dependent activation of the TBK1-type 1 IFN pathway and/or a TRAF6-dependent activation of the TAK1-proinflammatory cytokine pathway. The TRAF3-dependent activation of TBK1 and IKKε and TBK1-mediated activation of AKT result in the coordinate activation of the transcription factor IRF3, which translocates to the nucleus and induces the transcription of type 1 interferon genes upon activation. Pam3CSK4: tripalmitoyl-S-glycero-Cys-(Lys)4; Malp2: macrophage-activating lipopeptide-2; LPS: lipopolysaccharide; dsRNA: double-stranded RNA; ssRNA: single-stranded RNA; CpG: deoxycytidyl-phosphate-deoxyguanosine; MyD88: myeloid differentiation primary response gene 88; TIRAP: TIR domain-containing adaptor protein; TRAM: TRIF-related adaptor molecule; TRIF: TIR domain-containing adaptor inducing IFNβ; TRAF: TNFR-associated factor; IRAK: IL1R-associated kinase; TAK: transforming growth factor beta-activated kinase 1; TAB: TAK1-binding protein; IKK: inhibitor of nuclear factor kappa-B kinase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; IκB: inhibitor of NFκB; TBK1: TANK binding kinase 1; AMPs: antimicrobial peptides.

Figure 2

Proposed model for the role of TLR-mediated innate immune events in regulating the Th1/Th17 and Th2 immune balance. The development of Th1/Th17 T cells can be initiated upon innate immune activation of several TLRs, including TLR3 and MAVS (mitochondrial antiviral signaling protein) in keratinocytes (KCs), TLR7 and TLR9 in pDCs, TLR8 in cDCs, TLR2 in KCs and monocytes (Mon), and TLR4 in monocytes. Activation of these TLR-mediated signaling events leads to elevated expression of proinflammatory cytokines, type 1 interferons (including IFNβ from KCs and IFNα from pDCs), antimicrobial peptides (AMP), and costimulatory molecules (on cDCs and pDCs), which ultimately promote the differentiation of T cells from the Th0 to Th1/Th17 phenotype. In contrast, impaired TLR2 may play a role in the development of Th2 immune response. Genetic factors (such as TLR2 polymorphisms) or lack of early childhood exposure to microbes impairs TLR2 expression, and the resultant defective TLR2 signaling leads to decreased expression of antimicrobial peptides (AMPs), compromised epithelial barrier integrity, and decreased expression of Th1/Th17 cytokines. Impaired barrier integrity plays a central role in driving the allergic Th2 immune response by allowing allergens to penetrate through the skin surface. In addition, lack of AMP expression in the skin epidermis promotes dysbiosis of the skin microbiome and overgrowth of S. aureus, which releases several virulent toxins that exacerbate the disruption of barrier integrity and the expression of inflammatory Th2 cytokines. Activation of the Th1/Th17 immune system is necessary to promote autoimmunity and host defense against pathogens and cancer cells, but overstimulation of the Th1/Th17 pathway drives the development of several autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and fibrotic skin diseases (e.g., hypertrophic scarring and systemic sclerosis (SSc)). On the other hand, activation of the Th2 immune system is necessary to elicit normal allergic immune responses to allergens or pathogens, but overstimulation of Th2 immune response early in life initiates the progression of allergic diseases including atopic dermatitis, asthma, and allergic rhinitis, a pathological process known as “atopic march.”