Toll-Like Receptors in Dermatology, Venereology, and Leprosy.

Toll-like receptors (TLRs) represent a family of Type I transmembrane proteins characterized by an extracellular leucine-rich repeat domain and a cytoplasmic domain. TLRs represent a conserved group of receptors which help the immune system to function properly. Different TLRs are associated with an array of skin diseases. TLR agonists and antagonists have great potential for the treatment of allergic and inflammatory diseases. Copyright:

Introduction

The immune system has two lines of defense: innate and adaptive immunity. Innate immunity is the first immunological, antigen-dependent nonspecific mechanism against a pathogen. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific; it has the capacity for memory, which enables the host to mount a more rapid and efficient immune response on subsequent exposure to the antigen.[1]

In response to a pathogen exposure, a host employs both the innate and adaptive arms of the immune system to protect against infection. The innate immune response utilizes physical barriers such as skin and mucosal epithelium as a means of avoiding infection and rapid cellular responses enacted by dendritic cells (DCs), monocytes, natural killer cells, granulocytes, and epithelial cells to protect a newly infected host. These cells express pattern recognition receptors that mediate responses to pathogen-associated molecular patterns (PAMPs) that are conserved among microorganisms. Human toll like receptors (TLRs) are one such family of pattern recognition receptors that are capable of initiating innate immune responses and influencing subsequent adaptive immune responses.[2]

Definition

TLRs represent a family of type I transmembrane proteins characterized by an extracellular leucine-rich repeat domain and a cytoplasmic domain, similar to interleukin-1 (IL-1) receptor.[3]

History

The name “TLR” is derived from the structural and functional resemblance to a transmembrane receptor discovered in Drosophila melanogaster flies. Toll is a regulator for Drosophila embryonic development, responsible for the determination of the dorsoventral axis of the insect.[4] The German word “Toll” (”fantastical” or “strange”) was used by the German research group which discovered that flies with mutant forms of this protein took on a severely distorted phenotype.[5] In 1997, Medzhitov et al. described the first human homolog of the Drosophila toll receptor, which is now known as TLR4.[2]

Structure

TLRs are transmembrane proteins with the extracellular portion composed of horseshoe-shaped leucine-rich repeats, whereas the intracellular portion shares homology with the cytoplasmic domain of the IL-1 receptor[6] [Figure 1].

Figure 1

Structure of toll-like receptor

Activation pathway

Effects of toll-like receptor activation

TLR activation promotes phagocytosis of pathogens and inflammatory responses to phagosome contents as well as the maturation of phagosomes, allowing for the killing of phagocytosed bacteria[9]

TLR activation triggers antimicrobial pathways that promote the release of nonspecific antibacterial molecules such as antimicrobial peptides[10]

Furthermore, TLR activation facilitates and instructs the development of adaptiveimmune responses by increasing the levels of expression of co-stimulatory molecules such as CD80 and CD86 on dendritic cells, allowing dendritic cells to activate T-cells and releasecytokines[11]

TLR activation may also lead to apoptosis.[12]

Toll-like receptor expression in skin

It appears that keratinocytes in different layers of the epidermis may express different TLRs. As keratinocytes progress from the basal layer to the surface of the skin, their patterns of TLR expression may also change. Antibody staining of the biopsies demonstrated cytoplasmic TLR1 and TLR2 expression throughout the epidermis with TLR2 staining most strongly on basal keratinocytes. The basal layer also demonstrated TLR5 staining.[13] Other studies report expression of TLR4 on keratinocytes. Antibody staining of skin sections demonstrated the presence of TLR2 and TLR4 throughout the epidermis [Table 1].[14]

Table 1

Characteristics of toll-like receptors

TLR	Receptor ligand	Function
TLR1	Triacylated lipopeptides	Protection against mycobacteria
TLR2	Peptidoglycan, bacterial lipoprotein, lipoteichoic acid, and LPS	Defense against Gram-positive bacteria, mycobacteria, mycoplasma, protozoa, and fungi
		Induction of apoptosis
		Mast cell activation and degranulation
TLR3	ds-DNA	Antiviral defense
TLR4	LPS(Gram-negative bacteria), HSP60, fibronectin	Defense against various Gram-negative bacteria, fungi, IFNs, and viruses
		Induction of apoptosis
TLR5	Flagellin	Defense against flagellated bacteria
		DC maturation
TLR6	MALP-2(mycoplasma), phenol-soluble modulin(Staphylococcus epidermidis)	Defense against bacteria, fungi, mycoplasma, and protozoa
TLR7	ssRNA, imiquimod, resimiquimod	Antiviral and antitumor defense
		DC maturation
		Activation and migration of LCs from skin to draining
		Activation and proliferation of Th1 cells, NK cell, B-cell, and eosinophil
TLR8	ssRNA, resiquimod	Same as TLR7
TLR9	CpG-DNA in bacteria and virus	Antibacterial and antiviral defense
		Th1 development
		B-cell proliferation
		DC maturation
TLR10	Not yet known	Unknown

DC: Dendritic cells, dsDNA: double stranded DNA, HSP60: Heat shock protein-60, IFN: Interferon, LPS: Lipopolysaccharide, ssRNA: single stranded RNA, TLR: Toll-like receptors, MALP 2: Macrophage-activating lipopeptide-2

Role of TLR receptors in dermatology, venereology and leprosy

TLRs have been found to have a role in pathogenesis of several conditions [Table 2].

Table 2

Applications of toll-like receptors in dermatology, venereology, and leprosy

Disease	Role of TLR
Acne vulgaris[15]	TLR2 expression is implicated in the pathogenesis of acne
Atopic dermatitis[1416]	Polymorphism of TLR2 and TLR9 is associated with increased susceptibility
Basal cell carcinoma[17]	TLR7, TLR8, and TLR9 is associated with exacerbation of disease
Behcet’s disease[14]	Polymorphism of TLR4 leads to increased susceptibility
	Differential regulation of TLR6 helps in progression of disease
Lyme disease[14]	Upregulation of TLR1/2, TLR4, and TLR6 is associated with eventual exacerbation of the disease
Herpes simplex[1418]	TLR2 polymorphism is associated with disease severity while TLR3 and TLR9 help in viral clearance
Leprosy[1819]	The tuberculoid form of the disease more strongly expressed TLR2 and TLR1 within the lesion as compared with patients with lepromatous leprosy, suggesting that lepromatous patients may not beas able to activate cellular immune responses
Lichen planus[1820]	Upregulation of TLR9 is associated with eventual exacerbation of the disease
Lupus erythematosus[21]	TLR7 upregulation and TLR3*, TLR9 function helps to create autoreactive cells
Molluscum contagiosum[22]	Molluscum contagiosum skin lesions have been shown to express TLR3 and TLR9
Melanoma[14]	TLR4 exacerbates disease
Psoriasis[1323]	Upregulation of TLR1-4, TLR5, and TLR9 helps in creation of autoreactive T-cells
Sarcoidosis[24]	Polymorphism of TLR2 and TLR4 is associated with disease severity
Systemic sclerosis[14]	TLR4 signaling leads to disease progression
Squamous cell carcinoma[14]	TLR7 and TLR8 are associated with exacerbation of disease
Staphylococcusaureus[14]	TLR2 polymorphism is associated with severity, while TLR2/6 function and signaling leads to disease progression
SJS/TEN[25]	TLR3 polymorphism is linked to disease severity
Verruca[22]	TLR3 and TLR9 help in immune activation, TLR7* has a possible association with disease exacerbation

TLR: Toll-like receptors, SJS/TEN: Steven Johnson syndrome/ Toxic epidermolytic necrolysis

Role of toll-like receptors in psoriasis

Psoriasis is a chronic inflammatory skin disease mediated by T-cells and characterized clinically by hyperproliferation of the epidermis. It was noted that TLR2 appeared to be more strongly expressed in the upper epidermis of psoriasis patients. Whereas TLR2 was more strongly expressed in the basal layers of normal and nonlesional skin. Furthermore, TLR5 expression was reduced in basal keratinocytes of lesions as compared with normal skin. Another group of investigators found that the basal keratinocytes of psoriatic skin demonstrated a strong and diffuse expression of TLR1.[26]

Role of toll-like receptors in leprosy

Patients with the tuberculoid form of the disease more strongly expressed TLR2 and TLR1 within the lesion as compared with patients with lepromatous leprosy, suggesting that lepromatous patients may not be as able to activate cellular immune responses. Thus, in leprosy, the activation and regulation of TLR2 and TLR1 at the site of disease may contribute to the host's defense against Mycobacterium leprae.[14]

Conclusion

TLRs represent a conserved group of receptors which help the immune system to function properly. Different TLRs are associated with an array of skin diseases. TLR agonists and antagonists have great potential for the treatment of allergic and inflammatory diseases. More research must discern the relationship between specific TLRs and the corresponding disease to harness the therapeutic potential of TLR ligands. Although studies have proven that TLR agonists such as CpG can induce a robust immune response, the efficacy of the vaccines, optimization of dosage, long-term effects, and augmentation requires further study.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.