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DOI: 10.1111/j.1468-3083.2011.04049.x
REVIEW ARTICLE
Abstract
Toll-like receptors are important pattern recognition receptors which have key roles in both innate and adaptive
immune responses. They are strongly associated with the pathogenesis of inflammatory and autoimmune diseases.
Furthermore, Toll-like receptors have also been implicated in the pathogenesis of several skin diseases such as skin
infections, psoriasis, acne vulgaris, lichen planus, Behcets disease, leprosy, syphilis, Lyme disease, atopic
dermatitis and allergic contact dermatitis, mycosis fungoides, non-melanoma skin cancers and melanoma. In this
manuscript, the structure and functions of Toll-like receptors in immune responses, their impact on skin diseases
and recent advances on therapeutic usage have been reviewed.
Received: 18 January 2011; Accepted: 16 February 2011
Conflict of interest
None declared.
Introduction
All living organisms are continuously exposed to foreign entities
including food, micro-organisms and unnecessary self metabolites.
There is a continuing need to discriminate dangerous non-self
from safe self, particularly when life-threatening microorganisms
invade the body. Two arms of immune defences against invading
pathogens: innate (natural) and adaptive (acquired) immunity
have been defined.1
Innate immunity is the first line of host defence. The innate
immune response utilizes both physical barriers such as skin and
mucosal epithelium for avoiding infection and rapid cellular
responses. Inflammatory responses by innate immune cells such
as granulocytes and macrophages that can be triggered in minutes
and are then followed by activation of dendritic cells and natural
killer (NK) cells.2,3 Adaptive (acquired) immune responses are
slower processes that are mediated by T cells and B cells, whose
highly diverse antigen receptors are generated by complex DNA
rearrangement events and thus have the potential to recognize
novel antigens as well as conserved ones. In contrast to adaptive
immunity, innate immunity had been regarded as a relatively nonspecific system, with its main roles being to engulf and destroy
pathogens, to trigger proinflammatory responses, and to help
present antigen, thereby priming adaptive immune responses.1
However, recent studies showed that the innate immune system
has a great degree of specificity that enables it to discriminate efficiently between self and foreign entities, including microorganisms
and unnecessary self molecules.1,4 Innate immune system recognizes pathogens by pathogen-associated molecular patterns
(PAMPs), including molecules from Gram-positive and -negative
bacteria, DNA and RNA viruses, fungi and protozoa and they
show target specificity.2,5 The mammalian receptors responsible
for recognition of PAMPs are called pattern recognition receptors
(PRRs). The failure of the immune system to recognize a pathogens PAMP could lead to a delay or blunting of the immune
response, resulting in unchecked invasion by the microbe.6 The
major pattern recognition receptors of the innate immune system
are Toll-like receptors (TLRs), Nod-like receptors (NLRs) and
RIG-I-like receptors (RLRs). Unlike the T-cell and B-cell antigen
receptors, these PRRs are entirely germline-encoded and are
expressed constitutively by both immune and non-immune cells.1
Following PAMP recognition, PRR activate specific signalling
pathways that lead to robust but highly defined innate immune
responses. These innate responses then help prime subsequent
protective adaptive (antigen-specific) immune responses to the
inciting pathogens.
In addition to their primary function of fighting invading
microbes, PRRs are also involved in the pathogenesis of many
diseases. In particular, PRR recognition of self-molecules derived
from the host (e.g. nucleic acids) may be linked to autoimmune
diseases and possibly to other immunological disorders. In
humans, PRRs and their mutations have recently been linked to
susceptibility, not only to infectious diseases, but also to chronic
inflammatory diseases, such as atherosclerosis and asthma.1,7 It
has been reported that TLRs play an important role in the pathophysiology of autoimmune, central nervous system (CNS), lung,
gastrointestinal tract, kidney diseases and cancer.2,811 There have
been significant advances in our understanding of TLRs in skin
inflammation, cutaneous malignancies and defence mechanisms.
Ermertcan et al.
998
Species
References
TLR1 + TLR2
(1,3)
TLR2
Zymosan
Fungi
(1,26,38)
TLR3
dsRNA
Viruses
TLR4
Lipopolysaccharide Gram-negative
bacteria
(3,8,12,26)
TLR5
Flagellin
Bacteria
(1,9,38)
TLR6 + TLR2
Diacyl lipopeptides
Mycoplasma
(1,14,18)
TLR7
ssRNA
Virus, host
(1,9,12,14,39)
TLR8
ssRNA
Virus, host
(1,9,12,14)
TLR9
DNA, hemozoin
TLR10
Not known
Bacteria
(1,38)
TLR11
Profilin-like protein
Toxoplasma,
bacteria
(1,10,14)
(3,12)
999
Ermertcan et al.
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Related TLRs
References
Acne vulgaris
TLR 2, 4
(2,12,13,41,42)
Psoriasis
TLR 14, 5, 9
(12,13,15,4649)
Atopic dermatitis
TLR 2, 9
(15,25,5255)
TLR 7, 8, 9
(7276)
Squamous cell
carcinoma
TLR 7, 8
(77,78)
Melanoma
TLR 4, 7, 9
(67,68)
S. aureus
TLR 2, 6
(14,15)
C. albicans
TLR 2, 4
(13,63)
Herpes simplex
Varicella zoster
TLR 2, 3, 9
(15,59,60,62)
Verruca Molluscum
contagiosum
TLR 3, 7, 9
(1,3,12)
Lyme disease
TLR 1 2
(heterodimers), 4, 6
(2,3,12)
Acne vulgaris
Leprosy
TLR 1, 2
(14,15,64,65)
Acne vulgaris is characterized by non-inflammatory and inflammatory lesions. TLR2 expression was detected in biopsy specimens,
particularly in perifollicular regions, and the number of TLR2positive cells increases in long-term disease.2 In addition, it has
been shown that there is a positive correlation between the severity
of acne lesions and the concentration of cells expressing TLR2.13
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. This demonstration of TLR2 expression at the site
of disease suggests that the inflammation triggered by P. acnes
through TLR2 may be an important factor in the pathogenesis of
acne.41,42 Keratinocytes and sebocytes, located near the piloseba-
Syphilis
TLR 2, 4 5
(heterodimer)
(12,13)
Lichen planus
TLR 9
(12)
Sarcoidosis
TLR 2, 4
(1,12)
Behcets disease
TLR 4, 6
(12)
Systemic lupus
erythematosus
TLR 2, 7, 9
(8,9)
Scleroderma
TLR 4
(12)
ceous unit, may be capable of detecting either pathogens or abnormal lipids. Human SZ95 sebocytes, in particular, express innate
immune molecules such as TLR2, TLR4, IL1b, IL6, IL8, CD1d and
1001
CD14. As a result of TLR stimulation due to P. acnes, proinflammatory cytokines, chemokines, antimicrobial lipids, antimicrobial
peptides and human b-defensin-2 are produced by these cells.12
Interestingly, topical retinoids which are used in the treatment of
acne, have been shown to decrease TLR2 expression.43,44 Nicotinamide, through interaction with TLR2 on keratinocytes significantly depresses IL8 production in a dose-dependent manner.45
Psoriasis
Psoriasis is a chronic inflammatory disease mediated by T cells. It
has been associated with Th1 and Th17 cytokine profiles. Keratinocytes from psoriatic plaques express high levels of TLRs 1, 2, 4,
5 and 9 compared with normal skin. Psoriatic lesions are very
resistant to superinfections by pathogens caused by the presence of
high levels of antimicrobial peptides in the psoriatic plaques. Activation of TLRs has been related to resistance to pathogenic microorganisms. TLR activation has also been implicated in the
exacerbation of the disease. In addition, the antimicrobial peptide
cathelicidin has been shown to present self-DNA to activate TLR9
on plasmacytoid dendritic cells leading to the production of
IFN-a, possibly promoting autoimmunity in psoriasis.12,13
Another growth factor important in psoriasis is TGF-a, which
up-regulates TLR5 and 9 expression and function in human
keratinocytes.46 Heat-shock proteins (i.e. HSP60) are suspected
immunogenic proteins that are heavily expressed by epidermal
keratinocytes of psoriasis. HSP60 may subsequently trigger TLR2
and 4 resulting with development and or aggravation of psoriasis.47,48 In psoriasis lesions, the expression of TLR1 and 2 on keratinocytes is further up-regulated. Keratinocytes in psoriatic skin,
activated by TLR 2, 3 and 4 ligands exhibited NFjB nuclear translocation and release of TNF-a and IL-8.49 TLR 7 and 8 signalling
have also been implicated in psoriatic exacerbations.47 It has been
Table 3 Therapeutic agents using in the treatment of skin diseases related with TLRs
Therapeutic agent
Related TLRs
References
Imidazoquinolinamines
TLR 7
(12,13)
TLR 7
Skin cancer
(12)
Imiquimod
Resiquimod
Immunomodulators
Loxoribine
Bropirimine
Calcineurin inhibitors
Atopic dermatitis
Pimecrolimus
TLR 2 6
Tacrolimus
TLR 1, 2
(87)
(56)
Nicotinamide
TLR 2
(45)
TLR 2, 4
Acne vulgaris
(88)
Adapalene
TLR 2
Acne vulgaris
(13)
Zinc salts
TLR 2
Acne vulgaris
(13)
TLR 4
(10)
CpG-ODN
TLR 9
Melanoma
(89,90)
Ermertcan et al.
1002
Skin infections
Staphylococcus aureus skin infections
Staphylococcus aureus causes infections, such as impetigo, folliculitis and cellulitis upon crossing the skin barrier. More severe infections, such as bacteraemia, sepsis and endocarditis can occur, too.
Several components of the bacteria, such as lipoproteins, peptidoglycans and lipoteichoic acid are agonists to TLR2 6 or TLR2 2.
Signalling pathway through TLR2 adapter molecule MyD88 and
the up-regulation of human b-defensin-3 are major contributors
to the immune response against S. aureus.13 In addition, several
in vivo studies in mice have demonstrated that TLR2-deficient
mice are more susceptible to S. aureus skin infection. This
provides evidence that TLR2 is important in host defence against
S. aureus infections in the skin.14,15 In a recent study performed by
Lai et al., they suggested that potential use of normal commensal
bacterium S. epidermidis may be helpful to activate TLR2 signalling and induce antimicrobial peptide expression, thus enabling
the skin to mount an enhanced response to pathogens.58
Herpes simplex virus and Varicella-Zoster virus
Clinical infections caused by Candida albicans include mucocutaneous infections as well as invasive and life-threatening infections
usually seen in immunocompromised patients.14 In vitro studies
have demonstrated that TLR2 recognizes the Candida albicans cell
wall surface glycolipid phospholipomannan and TLR4 recognizes
the Candida albicans cell wall polysaccharide manan.63 Activation
of TLRs by Candida albicans induces the production of proinflammatory cytokines, candidicidal effector molecules and chemoattractant molecules to recruit other inflammatory molecules to
the site of infection.13
Leprosy
Ultraviolet injury
UVB radiation stimulates the up-regulation of HSPs from keratinocytes exposed to UVB. These HSPs are capable of binding to
TLRs 2 and 4 and stimulating the Toll IL-1 pathway in dendritic
cells. This signalling induces the downstream production of
1003
Melanoma
Melanoma is a malignant tumour of melanocytes which exposure
to UV radiation is the main risk factor for the disease. Melanocytes have the ability to help tumour progression in melanoma
by responding to hyaluronic acid fragments through TLR4 by
inducing MMP and cytokine production. Although melanocytes
have been shown to express other TLRs, TLR9 has been targeted
for modulating immune response.67,68 Many TLR ligands are
considered good adjuvant candidates as they can activate dendritic cells. TLR9 targeting appears to be a viable option in melanoma treatment. Different TLR9 agonists are now included in
vaccine formulations for human trials.69,70 Imiquimod, TLR7
agonist, was used to harness the potential TLR7 based treatment
for melanoma. It has found to be effective in both activating dendritic cells and producing tumour-specific cytotoxic T cells that
arrest disease progression.71
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1004
Conclusions
TLRs play a crucial role in the infectious diseases, inflammatory
diseases and cancer. TLRs have been shown to be important in
cutaneous host defence mechanisms in the skin. Different TLRs
are associated with the pathogenesis of several skin diseases. Development of TLR-based therapies for skin diseases and skin cancer
has gained interest by understanding of the TLR signalling and
discovery of topical TLR agonists, especially imiquimod.
Future research is necessary on the relationship between TLRs
and skin diseases, and TLR-based treatments. The success of these
therapies will require detailed and multidisciplinary trials for optimization of dosage, long-term effects and side effects. As dysregulation of TLR signalling has been shown, we hope that therapeutic
manipulation of TLRs may be used for anti-ageing strategies.
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