Indian Journal of Dermatology
E-IJDŽ-RESIDENT PAGE
Year
: 2021  |  Volume : 66  |  Issue : 2  |  Page : 223-

Toll-like receptors in dermatology, venereology, and leprosy


Sneha Gandhi1, K Ravindra2,  
1 Department of Dermatology, Venereology and Leprosy, GIMS, Gulbarga, Karnataka, India
2 Department of Dermatology, Venereology and Leprosy, JJMMC, Davangere, Karnataka, India

Correspondence Address:
Sneha Gandhi
GIMS, Gulbarga, Karnataka
India

Abstract

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.



How to cite this article:
Gandhi S, Ravindra K. Toll-like receptors in dermatology, venereology, and leprosy.Indian J Dermatol 2021;66:223-223


How to cite this URL:
Gandhi S, Ravindra K. Toll-like receptors in dermatology, venereology, and leprosy. Indian J Dermatol [serial online] 2021 [cited 2021 Nov 29 ];66:223-223
Available from: https://www.e-ijd.org/text.asp?2021/66/2/223/313786


Full Text



 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}

Activation pathway

[INLINE:1]

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 adaptive immune 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 release cytokines[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}

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}

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

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 2011;7 Suppl 1:S1.
2Medzhitov R, Preston-Hurlburt P, Janeway CA Jr., A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 1997;388:394-7.
3Belvin MP, Anderson KV. A conserved signaling pathway: The Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol 1996;12:393-416.
4Anderson KV, Nüsslein-Volhard C. Information for the dorsal – Ventral pattern of the Drosophila embryo is stored as maternal mRNA. Nature 1984;311:223-7.
5Cohen B. Nobel committee rewards pioneers of development studies in fruitflies. Nature 1995;377:465.
6Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335-76.
7Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, et al. Severe impairment of interleukin-1 and toll-like receptor signalling in mice lacking IRAK-4. Nature 2002;416:750-6.
8Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF-kappaB activation and complex formation with ikappaB kinase-alpha and NIK. Science 1997;278:866-9.
9Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, et al. The toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 1999;401:811-5.
10Hertz CJ, Wu Q, Porter EM, Zhang YJ, Weismüller KH, Godowski PJ, et al. Activation of toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. J Immunol 2003;171:6820-6.
11Michelsen KS, Aicher A, Mohaupt M, Hartung T, Dimmeler S, Kirschning CJ, et al. The role of toll-like receptors (TLRs) in bacteria-induced maturation of murine dendritic cells (DCs). Peptidoglycan and lipoteichoic acid are inducers of DC maturation and require TLR2. J Biol Chem 2001;276:25680-6.
12Choi KB, Wong F, Harlan JM, Chaudhary PM, Hood L, Karsan A, et al. Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway. J Biol Chem 1998;273:20185-8.
13Baker BS, Ovigne JM, Powles AV, Corcoran S, Fry L. Normal keratinocytes express toll-like receptors (TLRs) 1, 2 and 5: Modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 2003;148:670-9.
14Hari A, Flach TL, Shi Y, Mydlarski PR. Toll-like receptors: Role in dermatological disease. Mediators Inflamm 2010;2010:437246.
15Koreck A, Pivarcsi A, Dobozy A, Kemény L. The role of innate immunity in the pathogenesis of acne. Dermatology 2003;206:96-105.
16Hasannejad H, Takahashi R, Kimishima M, Hayakawa K, Shiohara T. Selective impairment of toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol 2007;120:69-75.
17Stockfleth E, Trefzer U, Garcia-Bartels C, Wegner T, Schmook T, Sterry W, et al. The use of toll-like receptor-7 agonist in the treatment of basal cell carcinoma: An overview. Br J Dermatol 2003;149 Suppl 66:53-6.
18Kang SS, Kauls LS, Gaspari AA. Toll-like receptors: Applications to dermatologic disease. J Am Acad Dermatol 2006;54:951-83.
19Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW, Legaspi A, et al. Activation and regulation of toll-like receptors 2 and 1 in human leprosy. Nat Med 2003;9:525-32.
20Li J, Chen J, Tan Z, Liu H, Liu Z. Expression of TLR9 and its mRNA in the lesions of lichen planus. J Huazhong Univ Sci Technolog Med Sci 2007;27:203-5.
21Means TK, Luster AD. Toll-like receptor activation in the pathogenesis of systemic lupus erythematosus. Ann N Y Acad Sci 2005;1062:242-51.
22Ku JK, Kwon HJ, Kim MY, Kang H, Song PI, Armstrong CA, et al. Expression of toll-like receptors in verruca and molluscum contagiosum. J Korean Med Sci 2008;23:307-14.
23Begon E, Michel L, Flageul B, Beaudoin I, Jean-Louis F, Bachelez H, et al. Expression, subcellular localization and cytokinic modulation of toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin. Eur J Dermatol 2007;17:497-506.
24Wikén M, Grunewald J, Eklund A, Wahlström J. Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis. J Clin Immunol 2009;29:78-89.
25Ueta M, Sotozono C, Inatomi T, Kojima K, Tashiro K, Hamuro J, et al. Toll-like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. Br J Ophthalmol 2007;91:962-5.
26Curry JL, Qin JZ, Bonish B, Carrick R, Bacon P, Panella J, et al. Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 2003;127:178-86.