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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Adv Dermatol. Author manuscript; available in PMC Nov 1, 2009.
Published in final edited form as:
Adv Dermatol. 2008; 24: 71–87.
doi:  10.1016/j.yadr.2008.09.004
PMCID: PMC2633625
NIHMSID: NIHMS84176

Toll-like receptors in skin

Abstract

The skin not only plays an important role as a physical barrier between the host and the environment, but also plays a key immunologic role in sensing and responding to invading pathogens from the environment. Toll-like receptors (TLRs), which are expressed by many different types of cells in human skin, have been found to be important pattern recognition receptors that are involved in recognizing components of microbial pathogens and initiating and instructing cutaneous immune responses. This review examines the similarities and differences among the ten known TLRs in humans. In addition, the role of TLRs in cutaneous host defense mechanisms against a variety of microorganisms, including bacteria, fungi, and viruses, as well as the involvement of TLRs in the pathogenesis of certain skin diseases will be discussed.

Keywords: Toll-like receptors, TLR, Skin, Cutaneous, Innate immunity, Immunology

Introduction

In addition to its role as a physical barrier between the host and the environment, the skin also has an important immunologic role in detecting invading pathogens (13). The skin immune system can be divided into early innate immune responses, which promote cutaneous inflammation and adaptive immune responses that promote memory responses against foreign antigens (4;5). Toll-like receptors (TLRs) are a recently identified group of pattern recognition receptors (PRRs) that are involved in mechanisms of host defense against a wide range of pathogenic microorganisms (68). TLRs are thought to function by detecting the presence of components of microorganisms and subsequently activating different gene programs, which promote various innate and adaptive immune responses (68). There are many different types of cells in the skin that express TLRs, including keratinocytes and Langerhans cells (LCs) in the epidermis, resident and trafficking immune system cells such as monocytes/macrophages, dendritic cells (DCs), T and B lymphocytes, and mast cells in the dermis, endothelial cells of the skin microvasculature, and stromal cells such as fibroblasts and adipocytes(3). All of the cells through their distinct expression of TLRs can recognize different components of microorganisms and initiate host defense mechanisms(3). Thus, TLRs expressed by cells in skin enable these cells to play an integral role in cutaneous immune responses against microbial pathogens. In addition, TLRs have been implicated in the pathogenesis of certain skin diseases (13).

Innate and adaptive immunity

Innate immunity was once considered to be an early nonspecific proinflammatory response whose primary function was to recruit and activate phagocytes such as neutrophils and monocytes/macrophages to phagocytize microorganisms (9;10). It is now known that the innate immune response has considerable specificity that is directed against conserved molecular patterns of components of microorganisms, which are called pathogen-associated molecular patterns (PAMPs) (9;10). The receptors on immune system cells that recognize PAMPs are called pattern recognition receptors (PRRs) (9;10). TLRs are a major class of PRRs and each TLR recognizes a different PAMP (see below) (610). In contrast, adaptive immunity is mediated by T and B lymphocytes, which have somatically generated receptors on their cell surface (4;6). The receptors of the adaptive immune system cells are not PRRs and do not recognize PAMPs, but instead recognize a diverse array of foreign antigenic components (4;6). These adaptive immunity receptors are generated by somatic hypermutation and genomic DNA recombination of antigen receptor gene segments (4;6). This process allows for a small number of genes to produce a vast array of different antigen receptors on each T and B lymphocyte with each receptor having a unique affinity for a given antigen (4;6). In addition, since the gene rearrangement is permanent, all of the progeny of a given T or B lymphocyte will express the same antigen receptor (4;6). This results in the production of “memory” T and B lymphocytes, which are responsible for mediating long-lived immunologic memory responses (4;6). Interestingly, T and B cells, in addition to expressing these adaptive immune receptors, also express TLRs, which can modify the immune responses generated by these cells (3). The early immune response to an invading pathogen is largely mediated by innate immunity whereas the subsequent cell-mediated and humoral immune responses and ensuing memory responses are mediated by T and B lymphocytes of the of the adaptive immune response (4;6).

Toll-like receptors

TLRs are transmembrane glycoproteins that contain an ectodomain of leucine-rich motifs, which is involved in recognition of components of microbes (68). TLRs also contain a transmembrane domain and a cytoplasmic tail domain that is homologous to the interleukin-1 receptor and is responsible for initiating various intracellular signaling cascades (Fig. 1) (68). These signaling cascades include activation of nuclear factor-κB (NF-κB), which is a key transcription factor that promotes expression of genes involved in immune responses such as cytokines, chemokines, and co-stimulatory and adhesion molecules (68). Thus far, ten TLRs have been identified in humans (Fig. 2) (68). Interestingly, each TLR recognizes a distinct PAMP (68). TLR2 can form a heterodimer with either TLR1 or TLR6 to recognize tri- or diacyl lipopeptides of bacteria, respectively (68). TLR2/6, along with CD36, has also been shown to recognize lipoteichoic acid (which is diacylated) of Gram-positive bacteria (68). TLR2 can also recognize peptidoglycan of most bacterial species and can also components of fungi (68). TLR3 recognizes double-stranded RNA (dsRNA), which is found during the replication cycle of most viruses (68). TLR4 along with CD14 recognizes lipopolysaccharide (LPS) of Gram-negative bacteria (68). TLR5 recognizes bacterial flagellin (68). TLR7 and TLR8 recognize single-stranded RNA (ssRNA) found in certain viruses and also recognizes the imidazoquinoline compounds, imiquimod and resiquimod (R-848) (68;11). Imiquimod (Aldara®) is the first TLR ligand that has been used to treat human disease. Imiquimod is FDA-approved to treat genital warts, actinic keratoses, and superficial basal cell carcinomas (11;12). TLR9 recognizes hypomethylated CpG motifs of bacterial double-stranded DNA (dsDNA) and DNA generated during the replication process of dsDNA viruses such as herpes simplex virus(68). The PAMP recognized by TLR10 is unknown.

Figure 1
TLRs and the interleukin-1 receptor share a similar signaling cascade to initiate immune responses
Figure 2
Pathogen-associated molecular patterns (PAMPs) recognized by TLRs, the cellular location of TLRs and the different MyD88 adapters used by TLRs that promote distinct immune responses

TLRs can also be classified into two groups based upon cellular location (Fig. 2) (68). TLRs 1, 2, 4, 5 and 6 are found on the cell membrane and can be activated by extracellular PAMPs. In contrast, TLRs 3, 7, 8 and 9 are found in membranes of intracellular compartments, such as endosomes and lysosomes (68). The intracellular location of TLRs 3, 7, 8 and 9 enable them to detect nucleic acids (i.e. DNA or RNA) that have been released from viruses or bacteria that are degraded within endosomes and lysosomes inside the cell (68).

Toll-like receptor signaling and immune responses

Activation of TLRs by their ligands results in initiation of several signaling cascades, which eventually result in expression of cytokines (e.g. TNFα, IL-1β, IL-6, IL-12), chemokines (IL-8, GRO-α, MCP-1, -2, -3, -4, MIP1α/β, and RANTES), anti-microbial peptides, (beta-defensins and cathelicidin), co-stimulatory molecules (CD40, CD80 and CD86), and adhesion molecules (ICAM-1) that are involved in innate and adaptive immune responses (Fig. 3) (68;13;14). In certain instances, TLRs can cause tissue injury in conditions such as sepsis, autoimmunity, and apoptosis of cells (7;13;14). The early signaling events initiated by TLR activation is mediated by members of the myeloid differentiation factor 88 (MyD88) family of adapter proteins (7;13;14). Activation of MyD88 adapters results in recruitment of interleukin-1 receptor-associated kinases (IRAKs) and tumor necrosis factor receptor-associated factors (TRAFs) (especially IRAK4 and TRAF6), which form the initial signaling complex (7;13;14). Formation of this complex eventually leads to activation of downstream signaling pathways, including activation of members of the MAP kinases (mitogen-activated protein kinases) such as ERK (extracellular-signal-regulated kinase), JNK (c-Jun-NH2-terminal kinase), and p38, and also activates transcription factors such as NF-κB and AP-1 (activator protein-1) (7;13;14). Activation of these pathways leads to expression of inflammatory cytokine genes and subsequent immune responses (68;13).

Figure 3
Immune responses generated by activation of TLRs

Interestingly, despite the common use of several signaling molecules, the different MyD88 adapter proteins are only utilized by certain TLRs (7;13;14). This difference in adapters leads to activation of distinct signaling pathways and gene programs that contribute to different cellular responses (Fig. 2). These different adapters include MyD88, TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein), TRIF (Toll-interleukin 1 receptor domain-containing adapter-inducing interferon-β) and TRAM (TRIF-related adapter molecule) (7;13;14). All of the TLRs, with the exception of TLR3, utilize MyD88 to initiate signaling (Fig. 2). In addition, TLRs 2 and 4 also require the presence of TIRAP (along with MyD88) to initiate signaling (7;13;14). Interestingly, TLR3 exclusively utilizes TRIF in a MyD88-independent pathway to initiate signaling (7;13;14). TLR4, in addition to utilizing MyD88, can also utilize TRIF (which in the case of TLR4 also requires the presence of TRAM) to initiate signaling (7;13;14). Utilization of the TRIF pathway by TLR3 or TLR4 results in the activation both NFκB and MAP kinases in a similar manner as the MyD88 pathway (7;13;14). However, TRIF, but not MyD88, specifically activates interferon (IFN)-regulatory factors 3 and 7 (IRF3/7), which promote production of type I interferon (i.e. IFNα and IFNβ) (7;13;14). These type I interferon responses are critical in the immune response against viruses (68;13;14).

Even though TLRs are PRRs and are thought to be involved in the early sensing of an infection during the innate immune response, TLRs also can instruct subsequent adaptive immune responses (6). For example, activation of TLRs on dendritic cells (DCs) can promote upregulation of co-stimulatory molecules such as CD40, CD80, and CD86 and production of IL-12 (6). CD80 and CD86 are important co-stimulatory molecules that help promote interaction and stimulation of antigen specific T cells of the adaptive immune response (6). In addition, IL-12 produced by TLR-stimulated DCs specifically promotes the induction of T helper 1 (Th-1) cell-mediated immune responses (6). Thus, in certain instances, TLR activation can instruct adaptive immune responses by inducing a Th-1 type immune response (6).

Toll-like receptors can induce a vitamin D-dependent antimicrobial pathway

Recently, Liu et al. demonstrated that activation of TLR2/1 on human monocytes/macrophages upregulated a vitamin D-1-hydroxylase (CYP27B1) and the vitamin D receptor (VDR) (15;16) (Fig. 4). This activity of TLR2/1 resulted in the conversion of the inactive form of vitamin D (25D3) to its active form (1,25D3), which subsequently activated the VDR and led to the production of the antimicrobial peptide cathelicidin (15;16). Since cathelicidin has microbicidal activity against a variety of pathogenic microorganisms, TLR2 induction of a vitamin D-dependent antimicrobial pathway may be an important mechanism for host defense. Similarly, Schauber et al. demonstrated that wounding of skin or stimulation of keratinocytes with TGF-β resulted in increased expression of TLR2 and CYP27B1 expression by keratinocytes (Fig. 4) (17). This resulted in increased cathelicidin expression via a vitamin D-dependent pathway (17). Taken together, these studies demonstrate that TLRs can increase cellular antimicrobial responses via a vitamin D-dependant pathway and represent another way that TLRs can protect the skin against infection.

Figure 4
TLR2 activates a vitamin D-dependent antimicrobial pathway

Toll-like receptor expression and function of skin-specific cells

There are many different cell types in human skin that express TLRs (13). In the epidermis, keratinocytes have been shown to express functional TLRs. In addition, there are resident and trafficking immune system cells in the skin that express TLRs, including Langerhans cells (LCs), monocytes/macrophages, dendritic cells (DCs), T and B lymphocytes, and mast cells (13). Lastly, endothelial cells of the microvasculature and stromal cells such as fibroblasts and adipocytes also express TLRs (13). Each of these cell types have distinct TLR expression patterns and likely contribute to cutaneous immune responses (13). This section will discuss TLR expression and function on keratinocytes and Langerhans cells.

Keratinocytes

Keratinocytes of the epidermis not only play an important role in maintaining the physical barrier between the host and the environment, but also participate in cutaneous immune responses (5;18). In particular, keratinocytes have been shown to express TLRs 1–6 and 9, which can help keratinocytes act as first-responders against pathogenic microorganisms (17;1931). For example, activation of TLR2 on keratinocytes by S. aureus or its components, peptidoglycan and lipoteichoic acid, results in activation of NF-κB and subsequent production of the neutrophil chemotactic factor IL-8 and iNOS (26). Other studies have demonstrated that activation of TLR3 by its ligand, dsRNA (poly I:C), on human keratinocytes induced production of IL-8, TNFα, IL-18, and type I interferon (IFNα/β) and the development of Th-1 type immune responses (20;24;25;30;32). Since TLR3 is thought to play an important role in recognizing viral infections, keratinocytes via TLR3 activation may play an important role in anti-viral immune responses in skin. Other studies have also demonstrated that activation of TLR5 on human keratinocytes by its ligand, flagellin, resulted in production of TNFα, IL-8, and the antimicrobial peptides, human β-defensins 2 and 3 (hBD2 and hBD3) (25;32;33). Lebre et al. demonstrated that activation of TLR3 and TLR9 on keratinocytes (by poly I:C and CpG DNA, respectively) leads to selective production of the chemokines, CXCL9 and CXCL10, which promote memory T cell responses and production of type I interferon (25). Another study by Miller found that the keratinocyte growth and differentiation factor, TGFα, which is found at high levels in healing wounds, upregulated expression and function of TLR5 and TLR9 (27). Thus, TGFα may not only stimulate keratinocytes to repair the barrier after wounding, but may also increase the ability of keratinocytes to sense an infection via increasing their functional responsiveness to TLR ligands (27).

Langerhans cells

Langerhans cells (LCs) are a subset of dendritic cells (DCs) that are found in the epidermis. Langerhans cells express the protein, langerin, which is found in birbeck granules, the intracellular organelle of LCs. Several studies have demonstrated that LCs express TLRs and may participate in mediating TLR responses (3439). A previous study by Renn et al. demonstrated that LC-like DCs that were derived from human cord blood express mRNA for TLRs 1–10 (40). LC-like DCs were most responsive to TLR2 ligands and TLR7/8 ligands (40). Furthermore, activation of LC-like DCs by TLR3 stimulation resulted in production of type I interferon (IFNα/β), suggesting a role for LC-like DCs in anti-viral immunity (34;40). However, recently, a study by Flacher et al. demonstrated that freshly isolated LCs that were purified from human skin express only TLRs 1, 2, 3, 5, 6 and 10 (41). These skin LCs responded to ligands to TLR2, TLR3 and produced IL-6, IL-8, and TNFα, but not IL-12 or IFNα/β (41). Interestingly, in response to peptidoglycan stimulation, the skin-derived LCs produced the Th2 cytokine, IL-10, suggesting that LCs may play a role in tolerance against commensal Gram-positive bacteria (41). Taken together, there are significant differences among TLR expression and function of LC-like DCs and LCs purified from human skin, and the LCs purified from human skin appear to play an important role in immunologic tolerance.

Toll-like receptors in the pathophysiology of skin disease

Atopic dermatitis

Atopic dermatitis or eczema is an inflammatory skin disease that is associated with a hereditary predisposition to atopic conditions, which include allergic rhinitis, allergic keratoconjuntivitis, asthma, and eczema (5). Clinically, atopic dermatitis is characterized by the presence of inflammatory skin lesions that are extremely pruritic (5). Like other allergic diseases, the pathophysiology of atopic dermatitis involves a Th-2 type immune response in the skin. The role of TLRs in the pathophysiology of atopic dermatitis is not entirely understood. However, the skin lesions of atopic dermatitis are highly susceptible to superinfection by bacterial and viral pathogens, such as S. aureus and herpes simplex virus (4245). Several studies have demonstrated that the skin lesions of atopic dermatitis have decreased levels of various antimicrobial peptides (beta-defensins, cathelicidin, and dermcidin) as compared with normal skin or psoriatic skin lesions and these lower levels of antimicrobial peptides may contribute to the increased susceptibility to infection (4245). Recent studies have identified the presence of certain polymorphisms in TLRs or TLR signaling molecules in patients with atopic dermatitis. One study found that a specific polymorphism in TLR2 (R753Q), which was previously associated with a subset of patients with severe S. aureus infections (46), defined a group of atopic dermatitis patients with a severe phenotype (47). However, another study did not show an association with TLR2 polymorphisms among patients with atopic dermatitis (48). Other studies have demonstrated that polymorphism in the TLR9 promoter or in TOLLIP, an inhibitory adapter protein within the TLR pathway, were also associated with atopic dermatitis (49;50). Lastly, monocytes from patients with atopic dermatitis have been shown to have a significant impairment in TLR2-mediated production of proinflammatory cytokines (51). Taken together, polymorphisms in TLRs or TLR signaling molecules may impair the functional responsiveness of TLRs (especially TLR2 and TLR9) in patients with atopic dermatitis. This impairment in TLR function may contribute the increased susceptibility of lesions of atopic dermatitis to bacterial and viral superinfection and may also contribute to the pathophysiology of the disease.

Psoriasis

Psoriasis is an inflammatory skin disease that is characterized clinically by cutaneous erythematous plaques with thick slivery scale (5). Histologic examination of psoriasis lesions reveals epidermal hyperplasia (acanthosis), dilation of papillary dermal blood vessels, and a dermal inflammatory infiltrate composed of predominantly of T cells and histiocytes (5;52). In contrast to atopic dermatitis, psoriasis has been associated with a Th-1 cytokine profile and more recently a Th-17 cytokine profile (5;52). Also, it is well known that psoriatic plaques are highly resistant to superinfection by pathogenic bacteria such as S. aureus (53). This increased resistance to infection may be partly explained by the high levels of antimicrobial peptides found in psoriatic scales (42;43;54;55). In addition, several studies have found that keratinocytes in psoriatic lesions have increased levels of TLRs 1, 2, 4, 5 and 9 compared with normal skin (1921;27;56). As mentioned above, Miller et al., demonstrated that the keratinocyte growth factor TGFα, which is found at high levels in healing wounds and in psoriatic lesions, increased expression of TLRs 5 and 9 and increased TLR-dependent production of pro-inflammatory cytokines (e.g. IL-8) and beta-defensins (27). Therefore, TLRs may contribute to the increased levels of antimicrobial peptides and cutaneous immune responses in psoriatic lesions. Interestingly, a previous report demonstrated that topical application of the TLR7 agonist imiquimod induced the spreading of a psoriatic plaque (57). Thus, TLR activation may also play a role in the pathophysiology of psoriasis by exacerbating the disease process (57). Lastly, a recent study demonstrated that the antimicrobial peptide cathelicidin (LL-37), which is found at high levels in psoriatic skin, can convert otherwise non-stimulatory self-DNA into a potent activator of TLR9 on plasmacytoid DCs resulting in production of IFNα (58). This may be one important mechanism of how TLRs can promote autoimmunity in psoriasis (58).

Acne vulgaris

Acne vulgaris is an inflammatory skin disease that occurs mostly during adolescence and involves inflammation of the pilosebaceous unit. The anerobic bacterium Propionibacterium acnes has been associated with the inflammation in acne lesions. Kim et al. demonstrated that TLR2 on human monocytes can be activated by P. acnes in vitro, resulting in increased production of IL-12 and IL-8 (59). Furthermore, macrophages expressing TLR2 were found surrounding pilosebaceous units of histologic sections of acne lesions from patients (59). Interestingly, topical retinoids such as all-trans retinoic acid and adapalene, which are used clinically to treat acne, have been shown to decrease TLR2 expression (60;61). Liu et al. demonstrated that all-trans retinoic acid can decrease TLR2 expression and function on cultured human monocytes (60). Tenaud et al. demonstrated that adapalene can decrease TLR2 expression on epidermal keratinocytes of explants of normal human skin and explants of acne lesions (61). Thus, TLR2 has been implicated in the inflammatory process in acne vulgaris and topical retinoids may help decrease the inflammation in acne lesions by decreasing expression and function of TLR2.

Toll-like receptors in skin infections

Staphylococcus aureus

S. aureus is a Gram-positive bacterium that is the most common cause of bacterial skin infections in humans such as impetigo, folliculitis/furunculosis, and cellulitis. TLR2 has been shown to recognize various components of S. aureus, including peptidoglycan and lipopeptides (6264). In addition, the TLR2/6 heterodimer along with CD36 has been shown to recognize S. aureus lipoteichoic acid (65). A recent study demonstrated that TLR2 on primary human keratinocytes contributed to upregulation of human beta-defensin 3 (hBD3), which has potent microbicidal activity against S. aureus (66). Other studies in mice have shown that mice deficient in TLR2 developed larger skin lesions in response to S. aureus skin infection (65;67). However, mice deficient in MyD88-developed much larger lesions than TLR2-deficient mice, suggesting that other receptors that signal via MyD88 may be important in cutaneous host defense against S. aureus (67). Miller et al. determined that mice deficient in IL-1R, which also signals via MyD88, developed large lesions that closely resembled those of MyD88-deficient mice, suggesting that IL-1R may play a more prominent role in cutaneous host defense against S. aureus than TLR2 (67).

Mycobacterium leprae

M. leprae is an intracellular bacterium that causes the clinical disease leprosy (68). Clinically, leprosy has a broad clinical spectrum. The tuberculoid form has few skin lesions, rare bacteria seen by histology, and is associated with a Th-1 type cell-mediated immune response (68). In contrast, the lepromatous form has numerous skin lesions, readily detectable bacteria by histology and is associated with a Th-2 type antibody-mediated immune response (68). There is considerable evidence that TLRs are involved in the immune response against leprosy. In vitro studies by Krutzik et al. have found that lipoproteins from M. leprae mediate cellular activation via TLR2/1 (69). Furthermore, another study demonstrated that TLR2 induced apoptosis of Schwann cells, which may contribute to the nerve damage seen in leprosy patients (70). In addition, individuals with polymorphisms in TLR2, which impair TLR2 function, have been shown to have an increased susceptibility to leprosy and the development of lepromatous form (7173). In particular, peripheral blood leukocytes isolated from patients with these polymorphisms produced less TNFα and Th-1 cytokines (e.g. IL-2, IL-12, and IFNγ) and increased IL-10 levels compared with individuals without the polymorphism (71;72). Thus, TLR2 has shown to be important in host defense against M. leprae, but may also increase nerve damage seen in leprosy lesions by increasing apoptosis of Schwann cells.

Candida albicans

C. albicans is a fungal pathogen that causes mucocutaneous infections and even life-threatening infections, especially in immunocompromised individuals (74). TLR2 recognizes C. albicans phospholipomannan (75). In contrast, TLR4 recognizes C. albicans O-bound mannan (76). In human keratinocyte cultures, Pivarcsi et al. demonstrated that keratinocyte-induced killing of C. albicans was dependent upon TLR2 and TLR4 activation(28). These studies suggest that TLR2 and TLR4 not only can recognize components of C. albicans, but also play a role in keratinocyte antimicrobial activity against C. albicans.

Herpes simplex and varicella-zoster virus

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are viral pathogens of the Herpesviridae family of dsDNA viruses that commonly infect human skin and mucosa (77;78). Infections by either HSV and VZV typically result in grouped vesicles that ulcerate and then heal (77;78). VZV is responsible for the clinical manifestations of varicella (chicken pox) during the first exposure and zoster (shingles) during re-activation of latent viral infection (78). Several TLRs have been implicated in the immune response to HSV. Individuals with genital HSV infections who had polymorphisms in TLR2, which caused impairment of TLR2 activity, had increased viral shedding and more recurrent infections than patients without TLR2 polymorphisms (79). Furthermore, individuals deficient in TLR3 had increased spreading of HSV infection from keratinocytes to cranial nerves, resulting in an increased susceptibility to HSV encephalitis (80). In cultures systems, TLR2 and TLR9 have been shown to recognize HSV glycoproteins and HSV dsDNA, respectively, and promote production of inflammatory cytokines(8184). Similarly, TLR2 can be activated by VZV to induce production of proinflammatory cytokines (78). Taken together, there is evidence that TLRs 2, 3, and 9 are involved in the cutaneous innate immune response against HSV and VZV infections.

Toll-like receptor-based treatments of skin disease

Since activation of TLRs promote immune responses, there has been a growing interest in pharmacologic targeting of TLRs in the treatment of various medical conditions, including certain skin diseases and skin cancer. In fact, imiquimod 5% topical cream (Aldara®), which is a nucleoside analog and a TLR7 agonist, has already been FDA approved to treat genital warts, actinic keratoses and superficial basal cell carcinomas (85;86). Through activation of TLR7, imiquimod induces expression of proinflammatory cytokines such as IFNα, TNFα, IL-6, IL-8, and IL-12 that promote a Th-1 type immune response (85;86). Furthermore, imiquimod has shown to have pro-apoptotic activity against tumors, which may explain its activity against skin cancers such as basal cell carcinomas (86). In addition, other studies have demonstrated that TLR9 agonists (i.e. CpG oligodeoxynucleotides) can be used as adjuvants in anti-cancer vaccines, which may be important in promoting specific anti-cancer immune responses against malignant melanoma and perhaps other cancers (8789). Thus, pharmacologic targeting of the immunomodulatory effects of TLRs may provide a basis for future therapies or vaccine development against certain skin diseases, skin cancer, and infections.

Conclusions

TLRs have emerged as a major class of PRRs that are involved in detecting invading pathogens in the skin and initiating cutaneous immune responses. TLRs are expressed on many different cell types in the skin, including keratinocytes and Langerhans cells in the epidermis. Each TLR can recognize a different microbial component and there are differences among the TLR signaling pathways, which lead to distinct immune responses against a given pathogen. Certain TLRs have been implicated in the pathogenesis of skin diseases, such as atopic dermatitis, psoriasis, and acne vulgaris. In addition, TLRs have been shown to be important in cutaneous host defense mechanisms against common bacterial, fungal, and viral pathogens in the skin, such as S. aureus, C. albicans, and HSV. Since the discovery that topical TLR agonists promote anti-viral and anti-tumor immune responses, there has been considerable interest in the development of TLR-based therapies for skin diseases, skin cancer and infections. Future research involving TLRs in skin will hopefully provide new insights into host defense against skin pathogens and novel therapeutic targets aimed at treating skin disease and skin cancer.

Footnotes

Dr. Miller and his colleagues at the University of California - Los Angeles have been national leaders in elucidating the roles of a family of proteins called Toll-like receptors (TLRs) in processes as diverse as Staphylococcus aureus skin infections, acne vulgaris, and leprosy infection. TLRs are a highly conserved family of pattern recognition receptors that have emerged as critical sensors of bacterial, fungal and viral pathogens by recognizing conserved components of these microorganisms, such as bacterial lipopeptides and virally-derived single-stranded and double-stranded RNA. The mechanism of action of current FDA-approved drugs, such as imiquimod, are based on the ability of these agents to activate TLRs. Agents that activate TLRs may also be very helpful in cancer therapy as vaccine adjuvants; conversely, inhibition of TLR-mediated signaling may help to down-regulate unwanted inflammation. Interestingly, TLRs have been implicated in cutaneous immune responses against a wide range of skin infections, including infections caused by Staphylococcus aureus, Mycobacterium leprae, Candida albicans, and viruses such as herpes simplex and varicella-zoster, and may contribute to the pathophysiology of common skin diseases such as atopic dermatitis, psoriasis, and acne vulgaris. Therefore, understanding the biology of the TLRs may give us new insights and, potentially, treatments for a variety of skin conditions.

Sam Hwang

Financial Disclosures

The author has no financial conflicts of interest.

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