The Role of Toll-like Receptors in the Pathogenesis and Treatment of Dermatological Disease
2005; Elsevier BV; Volume: 125; Issue: 1 Linguagem: Inglês
10.1111/j.0022-202x.2004.23459.x
ISSN1523-1747
AutoresJamie E. McInturff, Robert L. Modlin, Jenny Kim,
Tópico(s)Immune Cell Function and Interaction
ResumoToll-like receptors (TLR) are crucial players in the innate immune response to microbial invaders. These receptors are expressed on immune cells, such as monocytes, macrophages, dendritic cells, and granulocytes. Importantly, TLR are not only expressed by peripheral blood cells, but their expression has been demonstrated in airway epithelium and skin, important sites of host–pathogen interaction. Host cells expressing TLR are capable of recognizing conserved pathogen-associated molecular patterns, such as lipopolysaccharide and CpG DNA, and their activation triggers signaling pathways that result in the expression of immune response genes and cytokine production. As TLR are instrumental in both launching innate immune responses and influencing adaptive immunity, regulation of TLR expression at sites of disease such as in leprosy, acne, and psoriasis may be important in the pathophysiology of these diseases. Furthermore, since TLR are vital players in infectious and inflammatory diseases, they have been identified as potential therapeutic targets. Indeed, synthetic TLR agonists such as imiquimod have already established utility in treating viral pathogens and skin cancers. In the future, it seems possible there may also be drugs capable of blocking TLR activation and thus TLR-dependent inflammatory responses, providing new treatment options for inflammatory diseases. Toll-like receptors (TLR) are crucial players in the innate immune response to microbial invaders. These receptors are expressed on immune cells, such as monocytes, macrophages, dendritic cells, and granulocytes. Importantly, TLR are not only expressed by peripheral blood cells, but their expression has been demonstrated in airway epithelium and skin, important sites of host–pathogen interaction. Host cells expressing TLR are capable of recognizing conserved pathogen-associated molecular patterns, such as lipopolysaccharide and CpG DNA, and their activation triggers signaling pathways that result in the expression of immune response genes and cytokine production. As TLR are instrumental in both launching innate immune responses and influencing adaptive immunity, regulation of TLR expression at sites of disease such as in leprosy, acne, and psoriasis may be important in the pathophysiology of these diseases. Furthermore, since TLR are vital players in infectious and inflammatory diseases, they have been identified as potential therapeutic targets. Indeed, synthetic TLR agonists such as imiquimod have already established utility in treating viral pathogens and skin cancers. In the future, it seems possible there may also be drugs capable of blocking TLR activation and thus TLR-dependent inflammatory responses, providing new treatment options for inflammatory diseases. dendritic cells Langerhans cells lipopolysaccharide Toll-like receptor In response to pathogen exposure, a host employs both the innate and adaptive arms of the immune system to protect against infection. The innate immune response utilizes both physical barriers such as skin and mucosal epithelium as a means of avoiding infection and rapid cellular responses enacted by dendritic cells (DC), 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 (PAMP) that are conserved among microorganisms. Human Toll-like receptors (TLR) are one such family of pattern recognition receptors capable of initiating innate immune responses and influencing subsequent adaptive immune responses (Medzhitov et al., 1997Medzhitov R. Preston-Hurlburt P. Janeway Jr., C.A. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature. 1997; 388: 394-397Crossref PubMed Scopus (4208) Google Scholar). Currently, 10 TLR are known to be expressed in humans, and the microbial ligands for many of these receptors have been identified (Figure 1). The ligands include molecules uniquely found in microbes such as bacterial cell wall components. More specifically, TLR4 mediates host responses to bacterial lipopolysaccharide (LPS) from Gram-negative bacteria such as Escherichia coli, whereas TLR2 mediates responses to peptidoglycan from Gram-positive bacteria such as Staphylococcus aureus (Poltorak et al., 1998Poltorak A. He X. Smirnova I. et al.Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene.Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6166) Google Scholar; Yoshimura et al., 1999Yoshimura A. Lien E. Ingalls R.R. Tuomanen E. Dziarski R. Golenbock D. Cutting edge: Recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2.J Immunol. 1999; 163: 1-5PubMed Google Scholar). In addition, TLR2/1 heterodimers mediate responses to tri-acylated lipoproteins, and TLR2/6 heterodimers mediate responses to di-acylated lipoproteins (Brightbill et al., 1999Brightbill H.D. Libraty D.H. Krutzik S.R. et al.Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors.Science. 1999; 285: 732-736Crossref PubMed Scopus (1370) Google Scholar; Ozinsky et al., 2000Ozinsky A. Underhill D.M. Fontenot J.D. et al.The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors.Proc Natl Acad Sci USA. 2000; 97: 13766-13771Crossref PubMed Scopus (1617) Google Scholar). Not all TLR, however, mediate innate responses to components of bacterial cell walls. For instance, TLR9 mediates the response to unmethylated CpG DNA found in bacterial genomes, whereas TLR3 mediates the response to viral double-stranded RNA (Hemmi et al., 2000Hemmi H. Takeuchi O. Kawai T. et al.A Toll-like receptor recognizes bacterial DNA.Nature. 2000; 408: 740-745Crossref PubMed Scopus (5105) Google Scholar; Alexopoulou et al., 2001Alexopoulou L. Holt A.C. Medzhitov R. Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.Nature. 2001; 413: 732-738Crossref PubMed Scopus (4615) Google Scholar). Furthermore, TLR5 is involved in mediating the host response to bacterial flagellin, and recently single-stranded RNA was identified as the ligand for TLR8 in humans and TLR7 in mice (Hayashi et al., 2001Hayashi F. Smith K.D. Ozinsky A. et al.The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.Nature. 2001; 410: 1099-1103Crossref PubMed Scopus (2642) Google Scholar; Diebold et al., 2004Diebold S.S. Kaisho T. Hemmi H. Akira S. Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science. 2004; 303: 1529-1531Crossref PubMed Scopus (2412) Google Scholar; Heil et al., 2004Heil F. Hemmi H. Hochrein H. et al.Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (2799) Google Scholar). TLR are transmembrane proteins with the extracellular portion composed of leucine-rich repeats, whereas the intracellular portion shares homology with the cytoplasmic domain of the IL-1 receptor. When TLR are activated by ligand exposure, the intracellular domain of the TLR may trigger a MyD88-dependent pathway that ultimately leads to the nuclear translocation of the transcription factor NFκB. NFκB then acts to modulate expression of many immune response genes (Takeda et al., 2003Takeda K. Kaisho T. Akira S. Toll-like receptors.Annu Rev Immunol. 2003; 21: 335-376Crossref PubMed Scopus (4549) Google Scholar). In MyD88-dependent signaling, MyD88 interacts with the Toll/IL-1 receptor (TIR) domain of the cytoplasmic portion of the TLR (Medzhitov et al., 1998Medzhitov R. Preston-Hurlburt P. Kopp E. Stadlen A. Chen C. Ghosh S. Janeway Jr., C.A. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways.Mol Cell. 1998; 2: 253-258Abstract Full Text Full Text PDF PubMed Scopus (1239) Google Scholar). This interaction then facilitates MyD88 association with IL-1 receptor-associated kinase (IRAK), a serine–threonine kinase, which in turn activates tumor necrosis factor receptor-activated factor 6 (TRAF6) (Suzuki et al., 2002Suzuki N. Suzuki S. Duncan G.S. et al.Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4.Nature. 2002; 416: 750-756Crossref PubMed Scopus (627) Google Scholar). TRAF6 may then activate the IKK complex that leads to the phosphorylation and consequent degradation of IκB. Once IκB is ubiquitinated and degraded, the transcription factor NFκB is available for nuclear translocation (Woronicz et al., 1997Woronicz J.D. Gao X. Cao Z. Rothe M. Goeddel D.V. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK.Science. 1997; 278: 866-869Crossref PubMed Scopus (1052) Google Scholar). Although an important player in innate immune responses, MyD88 is not required for recognition of some microbial ligands, and not all TLR signaling is completely MyD88- dependent (Figure 2). There is some evidence that TLR3 and TLR4 also trigger a MyD88-independent pathway that involves IRF-3 to ultimately produce interferon (IFN)-β (Doyle et al., 2002Doyle S. Vaidya S. O'Connell R. et al.IRF3 mediates a TLR3/TLR4-specific antiviral gene program.Immunity. 2002; 17: 251-263Abstract Full Text Full Text PDF PubMed Scopus (699) Google Scholar). Subsequent studies have revealed that the TLR4-mediated activation of IRF-3 involves the adaptor proteins TRIF and TRAM (Hoebe et al., 2003Hoebe K. Du X. Georgel P. et al.Identification of Lps2 as a key transducer of MyD88-independent TIR signalling.Nature. 2003; 424: 743-748Crossref PubMed Scopus (999) Google Scholar; Yamamoto et al., 2003aYamamoto M. Sato S. Hemmi H. et al.TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway.Nat Immunol. 2003; 4: 1144-1150Crossref PubMed Scopus (786) Google Scholar). Likewise, TRIF was also found to mediate TLR3-dependent activation of IRF-3, but TRIF has also been shown to mediate the TLR3-dependent MyD88-independent activation of NFκB through TRAF6 (Yamamoto et al., 2003bYamamoto M. Sato S. Hemmi H. et al.Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.Science. 2003; 301: 640-643Crossref PubMed Scopus (2361) Google Scholar; Jiang et al., 2004Jiang Z. Mak T.W. Sen G. Li X. Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.Proc Natl Acad Sci USA. 2004; 101: 3533-3538Crossref PubMed Scopus (294) Google Scholar). Furthermore, there are other receptors that act independently of MyD88 to recognize conserved microbial patterns. These include Nod1 and Nod2, which are intracellular receptors for peptidoglycan that act independently of TLR and MyD88 to activate NFκB (Girardin et al., 2003aGirardin S.E. Boneca I.G. Carneiro L.A. et al.Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan.Science. 2003; 300: 1584-1587Crossref PubMed Scopus (1180) Google Scholar, Girardin et al., 2003bGirardin S.E. Travassos L.H. Herve M. et al.Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2.J Biol Chem. 2003; 278: 41702-41708Crossref PubMed Scopus (508) Google Scholar; Inohara and Nunez, 2003Inohara N. Nunez G. NODs: Intracellular proteins involved in inflammation and apoptosis.Nat Rev Immunol. 2003; 3: 371-382Crossref PubMed Scopus (831) Google Scholar). TLR activation contributes to host inflammatory responses. The activation of NFκB allows for transcription of immunomodulatory genes, including the genes for various cytokines and chemokines. The production of cytokines and chemokines in turn triggers inflammation through the recruitment of host immune cells and activation of antimicrobial defenses. Although this may aid the host in clearing an infection, inflammation triggered through TLR may also harm the host through the damage of host tissues or the development of septic shock. TLR activation is also involved in the phagocytosis of pathogens by host cells. TLR have been shown to sample phagosomal contents and trigger production of inflammatory cytokines after activation by TLR ligands within the phagosome (Underhill et al., 1999Underhill D.M. Ozinsky A. Hajjar A.M. Stevens A. Wilson C.B. Bassetti M. Aderem A. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens.Nature. 1999; 401: 811-815Crossref PubMed Scopus (1170) Google Scholar). More recently, TLR activation has also been shown to trigger internalization of pathogens as well as induce the maturation of host phagosomes (Blander and Medzhitov, 2004Blander J.M. Medzhitov R. Regulation of phagosome maturation by signals from toll-like receptors.Science. 2004; 304: 1014-1018Crossref PubMed Scopus (793) Google Scholar). The mechanism behind TLR-induced phagocytosis has been shown to involve MyD88, IRAK4, and p38, resulting in the up-regulation of scavenger receptors (Doyle et al., 2004Doyle S.E. O'Connell R.M. Miranda G.A. et al.Toll-like Receptors Induce a Phagocytic Gene Program through p38.J Exp Med. 2004; 199: 81-90Crossref PubMed Scopus (317) Google Scholar). Thus, 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. Another consequence of TLR activation is the triggering of direct antimicrobial pathways that promote the release of non-specific antibacterial molecules such as antimicrobial peptides. For example, primary human airway epithelial cells demonstrate increased β-defensin-2 production in response to TLR2 agonists, and LPS also stimulates increases in β-defensin-2 expression by tracheobronchial epithelium (Becker et al., 2000Becker M.N. Diamond G. Verghese M.W. Randell S.H. CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium.J Biol Chem. 2000; 275: 29731-29736Crossref PubMed Scopus (279) Google Scholar; Hertz et al., 2003Hertz C.J. Wu Q. Porter E.M. 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: 6820-6826Crossref PubMed Scopus (249) Google Scholar; Wang et al., 2003Wang X. Zhang Z. Louboutin J.P. Moser C. Weiner D.J. Wilson J.M. Airway epithelia regulate expression of human beta-defensin 2 through Toll-like receptor 2.FASEB J. 2003; 17: 1727-1729Crossref PubMed Scopus (82) Google Scholar). Furthermore, stimulation of an in vitro reconstructed epidermis with LPS has been shown to increase keratinocyte production of human β-defensin-2 mRNA by 4-fold (Chadebech et al., 2003Chadebech P. Goidin D. Jacquet C. Viac J. Schmitt D. Staquet M.J. Use of human reconstructed epidermis to analyze the regulation of beta-defensin hBD-1, hBD-2, and hBD-3 expression in response to LPS.Cell Biol Toxicol. 2003; 19: 313-324Crossref PubMed Scopus (40) Google Scholar). Interestingly, antimicrobial peptides are not only induced through TLR, but they may also activate cells through TLR. For instance, murine β-defensin-2 has been shown to activate DC through TLR4 (Biragyn et al., 2002Biragyn A. Ruffini P.A. Leifer C.A. et al.Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2.Science. 2002; 298: 1025-1029Crossref PubMed Scopus (777) Google Scholar). Thus, TLR activation is capable of promoting antimicrobial peptide production, and the release of these peptides may trigger more TLR activation. Importantly, TLR activation can also lead to the production and release of reactive oxygen and nitrogen species that aid in killing intracellular pathogens such as Mycobacterium tuberculosis in mice (Thoma-Uszynski et al., 2001Thoma-Uszynski S. Stenger S. Takeuchi O. et al.Induction of direct antimicrobial activity through mammalian toll-like receptors.Science. 2001; 291: 1544-1547Crossref PubMed Scopus (571) Google Scholar). Furthermore, TLR activation facilitates and instructs the development of adaptive immune responses. One way TLR facilitate adaptive immunity is by increasing the levels of expression of co-stimulatory molecules such as CD80 and CD86 on DC, allowing the DC to more effectively activate T cells (Tsuji et al., 2000Tsuji S. Matsumoto M. Takeuchi O. et al.Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: Involvement of toll-like receptors.Infect Immun. 2000; 68: 6883-6890Crossref PubMed Scopus (349) Google Scholar; Michelsen et al., 2001Michelsen K.S. Aicher A. Mohaupt M. Hartung T. Dimmeler S. Kirschning C.J. Schumann R.R. 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: 25680-25686Crossref PubMed Scopus (242) Google Scholar). Another avenue through which TLR activation influences adaptive immunity is through the production and release of cytokines. An important aspect of cytokine production is that the specific cytokines produced may instruct differentiation of T cells into Th1 or Th2 subsets, which guide the pattern of adaptive response the host will launch against the pathogen. For instance, human monocyte-derived DC stimulated with lipopeptide from M. tuberculosis secrete IL-12 over IL-10, skewing the host's adaptive immune response toward a Th1 pattern, characterized by a cellular, cytotoxic T cell response (Thoma-Uszynski et al., 2000Thoma-Uszynski S. Kiertscher S.M. Ochoa M.T. et al.Activation of toll-like receptor 2 on human dendritic cells triggers induction of IL-12, but not IL-10.J Immunol. 2000; 165: 3804-3810Crossref PubMed Scopus (203) Google Scholar). In contrast, activation of an adaptive Th2 immune response by cytokines such as IL-10 and IL-4 is characterized by the involvement of B cells and antibody production. Thus, the activation of TLR on DC serves not only to activate an innate immune response to a pathogen but also to instruct the pattern of the host's ensuing adaptive immune response. TLR activation may also lead to apoptosis. LPS has been shown to induce apoptosis through TLR4 (Choi et al., 1998Choi K.B. Wong F. Harlan J.M. Chaudhary P.M. Hood L. Karsan A. Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway.J Biol Chem. 1998; 273: 20185-20188Crossref PubMed Scopus (138) Google Scholar). Furthermore, the 19 kDa lipoprotein from M. tuberculosis has been shown to trigger apoptosis in macrophages, and activation of TLR2/6 with Mycoplasmal lipoproteins has also been shown to induce apoptotic cell death (Lopez et al., 2003Lopez M. Sly L.M. Luu Y. Young D. Cooper H. Reiner N.E. The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2.J Immunol. 2003; 170: 2409-2416Crossref PubMed Scopus (215) Google Scholar; Into et al., 2004Into T. Kiura K. Yasuda M. et al.Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation.Cell Microbiol. 2004; 6: 187-199Crossref PubMed Scopus (121) Google Scholar). This activation of TLR2 with bacterial lipoproteins has been shown to signal apoptosis through MyD88, Fas-associated death domain protein, and caspase 8 (Aliprantis et al., 2000Aliprantis A.O. Yang R.B. Weiss D.S. Godowski P. Zychlinsky A. The apoptotic signaling pathway activated by Toll-like receptor-2.EMBO J. 2000; 19: 3325-3336Crossref PubMed Scopus (413) Google Scholar). Importantly, the induction of apoptosis in infected cells through TLR ligands may help the host in eliminating the infection. As mentioned earlier, TLR are expressed by various cells of the innate immune system such as monocytes, macrophages, DC, and granulocytes. Moreover, as TLR are key players in the innate response to pathogens, the expression and function of TLR at sites of host-pathogen interaction is critical for host defense. This allows recognition of pathogens before they invade the bloodstream or the tissues of internal organs. This is indeed the case as TLR expression has been demonstrated in the epithelial cells of the airway and gut. Given that the skin is another crucial interface for host encounters with microbial invaders, it seems appropriate that the skin express TLR to accomplish its job as a barrier to infection. One study has demonstrated that normal keratinocytes express TLR1, 2, and 5 (Baker et al., 2003Baker B.S. Ovigne J.M. Powles A.V. 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: 670-679Crossref PubMed Scopus (240) Google Scholar). This study utilized punch biopsies from regions of normal skin in psoriasis patients and normal breast skin obtained from donors with no known skin diseases. 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. Thus, it appears that keratinocytes in different layers of the epidermis may express different TLR; as keratinocytes mature as they progress from the basal layer to the surface of the skin, their patterns of TLR expression may also change. Although not detected in the study previously discussed, other studies report expression of TLR4 on keratinocytes.Pivarcsi et al., 2003Pivarcsi A. Bodai L. Rethi B. et al.Expression and function of Toll-like receptors 2 and 4 in human keratinocytes.Int Immunol. 2003; 15: 721-730Crossref PubMed Scopus (276) Google Scholar demonstrated TLR2 and TLR4 mRNA and protein expression in cultured human epidermal keratinocytes obtained from the skin of healthy individuals. Also, antibody staining of skin sections demonstrated the presence of TLR2 and TLR4 throughout the epidermis. Notably, the ability of Pivarcsi et al to detect TLR4 corroborates an earlier study that utilized cultured human keratinocytes derived from foreskin.Song et al., 2002Song P.I. Park Y.M. Abraham T. et al.Human keratinocytes express functional CD14 and toll-like receptor 4.J Invest Dermatol. 2002; 119: 424-432Crossref PubMed Scopus (159) Google Scholar detected TLR4 mRNA through both northern blot and quantitiative PCR analyses, and this TLR4 expression was shown to increase in response to treatment with LPS. In addition, flow cytometry revealed surface TLR expression on these keratinocytes, and immunostaining with TLR4 monoclonal antibody was positive. Moreover, this group demonstrated that the LPS-induced IL-8 expression by these keratinocytes was TLR4 dependent. Most recently,Mempel et al., 2003Mempel M. Voelcker V. Kollisch G. et al.Toll-like receptor expression in human keratinocytes: Nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not toll-like receptor 4 or platelet activating factor receptor dependent.J Invest Dermatol. 2003; 121: 1389-1396Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar reported that cultured primary human keratinocytes expressed TLR1,2,3,5, and 9, but TLR4,6,7, and 8 were undetectable. These conflicting reports make it unclear if keratinocytes constituitively express TLR4. Therefore, it seems additional studies are needed to clarify TLR expression in keratinocytes. Studies with keratinocytes have not only demonstrated the expression of TLR, but they have also shown the ability of keratinocytes to activate innate immune responses through their TLR. Stimulation with Candida albicans or heat-killed M. tuberculosis, which possess TLR-stimulatory molecules, strongly induced NFκB in cultured keratinocytes suggesting that keratinocytes are capable of launching TLR-mediated responses (Pivarcsi et al., 2003Pivarcsi A. Bodai L. Rethi B. et al.Expression and function of Toll-like receptors 2 and 4 in human keratinocytes.Int Immunol. 2003; 15: 721-730Crossref PubMed Scopus (276) Google Scholar). Furthermore, Mempel et al found stimulation of keratinocytes with Staphylococcus aureus caused translocation of NFκB and subsequent increased production of IL-8 and iNOS. This inflammatory response was found to be TLR2 dependent (Mempel et al., 2003Mempel M. Voelcker V. Kollisch G. et al.Toll-like receptor expression in human keratinocytes: Nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not toll-like receptor 4 or platelet activating factor receptor dependent.J Invest Dermatol. 2003; 121: 1389-1396Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). Thus, TLR are not merely present on keratinocytes but may be active participants in cutaneous defense through triggering NFκB activation and thus production of cytokines and chemokines. Induction of chemokines and cytokines through TLR activation promotes the recruitment of immune cells out of the circulation to sites of infection, such as the skin, and the modulation of immune cell behavior. TLR-activated keratinocytes are also capable of modulating the host's adaptive immune response.Lebre et al., 2003Lebre M.C. Antons J.C. Kalinski P. Schuitemaker J.H. van Capel T.M. Kapsenberg M.L. De Jong E.C. Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a Type-1 polarized phenotype in dendritic cells: Role of keratinocyte-derived tumor necrosis factor alpha, type I interferons, and interleukin-18.J Invest Dermatol. 2003; 120: 990-997Crossref PubMed Scopus (76) Google Scholar demonstrated that supernatants of TLR-stimulated keratinocytes induced the maturation of human monocyte-derived immature DC. These now-mature DC were found to promote Th1 immune responses from naïve T cells. Thus, keratinocytes may be able to influence the development of Th1 or Th2 adaptive immune responses to cutaneous pathogens. Furthermore, this suggests that keratinocytes, through their activation of DC, may play an important role in inflammation mediated by T cells in the skin. In summary, keratinocytes play dynamic roles in host defense that extend beyond their role as a physical barrier. Keratinocytes have been shown to produce cytokine and antimicrobial peptides, recruit neutrophils, and kill microbes such as C. albicans. It appears now that many of these abilities are due to the activation of their TLR. Although TLR expression at sites of host–pathogen interaction likely serves to protect the host from pathogens, unnecessary immune responses to commensal bacterial may harm the host. This concept is illustrated by studies of TLR expression in Langerhans cells (LC), unique DC found in the epidermis. In contrast to DC, LC have been shown to respond differently to microbial TLR ligands. For example, LPS is capable of inducing the maturation of DC but not LC. Moreover, stimulation with LPS leads to the upregulation of CD80, CD86, and HLA-DR on DC but not LC. One group linked this relative unresponsiveness of LC to lower levels of TLR expression on the LC (Takeuchi et al., 2003Takeuchi J. Watari E. Shinya E. et al.Down-regulation of Toll-like receptor expression in monocyte-derived Langerhans cell-like cells: Implications of low-responsiveness to bacterial components in the epidermal Langerhans cells.Biochem Biophys Res Commun. 2003; 306: 674-679Crossref PubMed Scopus (58) Google Scholar). More specifically, this group could not detect mRNA for TLR4 in LC, and the amount of mRNA encoding TLR2 found in LC was demonstrably less than that found in DC. The authors propose the diminution of TLR expression on LC found in skin, as compared with DC, may explain why commensal bacteria do not continuously trigger inflammatory responses in the skin. More recently, another group has also demonstrated differences in TLR expression and activation between LC and DC (Mitsui et al., 2004Mitsui H. Watanabe T. Saeki H. et al.Differential expression and function of Toll-like receptors in Langerhans cells: Comparison with splenic dendritic cells.J Invest Dermatol. 2004; 122: 95-102Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). LC were found to have much lower levels of TLR4 on their surfaces as compared with DC, and unlike DC their level of TLR4 expression was not upregulated after stimulation with LPS. In addition, stimulation with ligands for TLR2,4, and 9 matured splenic DC but not LC. Taken together these results suggest that the differences in expression and activation of TLR on LC may potentially explain why commensal bacteria do not continuously trigger inflammation in skin; however, greater knowledge of the role of TLR on LC is warranted before this theory may be considered a fact. Leprosy, a disease caused by infection with the organism mycobaterium varies widely in its clinical presentation, which can be correlated with the type of immune response the host has launched against M. leprae. The tuberculoid form of the disease is characterized by localized infection, granulomatous lesions, and the expression of type 1 cytokines that promote cell-mediated immunity. On the other end of the spectrum is the lepromatous form of the disease that is characterized by disseminated infection, disfiguring nodular lesions, and the expression of type 2 cytokines that promote a humoral immune response. A recent study demonstrated that heterodimers of TLR2/1 were activated by killed M. leprae (Krutzik et al., 2003Krutzik S.R. Ochoa M.T. Sieling P.A. et al.Activation and regulation of Toll-like receptors 2 and 1 in human leprosy.Nat Med. 2003; 9: 525-532Crossref PubMed Scopus (260) Google Scholar). Since earlier studies indicate TLR2/1 heterodimers recognize tri-acylated lipoproteins,
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