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• W2015336716 startingPage "940" @default.
• W2015336716 abstract "It is now clear that the epidermis has an active role in local immune responses in the skin. Keratinocytes are involved early in inflammation by providing first-line innate mechanisms and, in addition, can contribute to adaptive immune responses that may be associated with clinical disease. Moreover, keratinocytes are capable of enhancing and shaping the outcome of inflammation in response to stimuli and promoting particular types of immune bias. Through understanding the underlying mechanisms, the role of keratinocytes in disease pathogenesis will be further defined, which is likely to lead to the identification of potential targets for prophylactic or therapeutic intervention. It is now clear that the epidermis has an active role in local immune responses in the skin. Keratinocytes are involved early in inflammation by providing first-line innate mechanisms and, in addition, can contribute to adaptive immune responses that may be associated with clinical disease. Moreover, keratinocytes are capable of enhancing and shaping the outcome of inflammation in response to stimuli and promoting particular types of immune bias. Through understanding the underlying mechanisms, the role of keratinocytes in disease pathogenesis will be further defined, which is likely to lead to the identification of potential targets for prophylactic or therapeutic intervention. dendritic cell keratinocyte Langerhans cell natural killer Toll-like receptor T-regulatory cell thymic stromal lymphopoietin. The epidermis provides a structural barrier for many external challenges, yet is also able to provide active signals related to barrier compromise and distinguish different types of challenges. Through these mechanisms, KCs can significantly influence the resultant innate and adaptive immune responses. For example, KCs are known to express Fc receptors such as FcγRI, FcγRII, and FcγRIII (Tigalonowa et al., 1990Tigalonowa M. Bjerke J.R. Livden J.K. et al.The distribution of Fc gamma RI, Fc gamma RII and Fc gamma R III on Langerhans’ cells and keratinocytes in normal skin.Acta Derm Venereol. 1990; 70: 385-390PubMed Google Scholar; Cauza et al., 2002Cauza K. Grassauer A. Hinterhuber G. et al.FcgammaRIII expression on cultured human keratinocytes and upregulation by interferon-gamma.J Invest Dermatol. 2002; 119: 1074-1079Crossref PubMed Scopus (12) Google Scholar, as well as complement receptors, mannose receptor (Szolnoky et al., 2001Szolnoky G. Bata-Csorgo Z. Kenderessy A.S. et al.A mannose-binding receptor is expressed on human keratinocytes and mediates killing of Candida albicans.J Invest Dermatol. 2001; 117: 205-213Crossref PubMed Scopus (44) Google Scholar, and other molecules that potentially aid internalization such as α5β1 fibronectin–binding integrin (Pellegrini et al., 1992Pellegrini G. De Luca M. Orecchia G. et al.Expression, topography, and function of integrin receptors are severely altered in keratinocytes from involved and uninvolved psoriatic skin.J Clin Invest. 1992; 89: 1783-1795Crossref PubMed Google Scholar. Binding to these results in effective endocytosis and subsequent killing of bacteria, fungi, and viruses, as documented for a variety of pathogens, including Staphylococcus aureus (Kisich et al., 2007Kisich K.O. Howell M.D. Boguniewicz M. The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on beta-defensin 3.J Invest Dermatol. 2007; 127: 2368-2380Crossref PubMed Scopus (77) Google Scholar, Candida albicans (Csato et al., 1986Csato M. Bozoky B. Hunyadi J. et al.Candida albicans phagocytosis by separated human epidermal cells.Arch Dermatol Res. 1986; 279: 136-139Crossref PubMed Google Scholar; Szolnoky et al., 2001Szolnoky G. Bata-Csorgo Z. Kenderessy A.S. et al.A mannose-binding receptor is expressed on human keratinocytes and mediates killing of Candida albicans.J Invest Dermatol. 2001; 117: 205-213Crossref PubMed Scopus (44) Google Scholar, and Herpes simplex virus (Nicola et al., 2005Nicola A.V. Hou J. Major E.O. et al.Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway.J Virol. 2005; 79: 7609-7616Crossref PubMed Scopus (109) Google Scholar. In addition, KCs express a spectrum of innate recognition receptors that can screen the external environment and provide proinflammatory and chemotactic signals to immune cells in a case of pathogen invasion. Various studies have reported that KCs also express Toll-like receptors (TLRs) 1–6 and 10 (Baker et al., 2003Baker B.S. Ovigne J.M. Powles A.V. et al.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 (174) Google Scholar; 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: 1389-1396Crossref PubMed Scopus (171) Google Scholar; 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 (221) Google Scholar, Pivarcsi et al., 2004Pivarcsi A. Koreck A. Bodai L. et al.Differentiation-regulated expression of Toll-like receptors 2 and 4 in HaCaT keratinocytes.Arch Dermatol Res. 2004; 296: 120-124Crossref PubMed Scopus (32) Google Scholar; Flacher et al., 2006Flacher V. Bouschbacher M. Verronese E. et al.Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria.J Immunol. 2006; 177: 7959-7967Crossref PubMed Google Scholar; Lebre et al., 2007Lebre M.C. van der Aar A.M. van Baarsen L. et al.Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.J Invest Dermatol. 2007; 127: 331-341Crossref PubMed Scopus (181) Google Scholar; de Koning et al., 2010de Koning H.D. Rodijk-Olthuis D. van Vlijmen-Willems I.M. et al.A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis.J Invest Dermatol. 2010; 130: 2611-2620Crossref PubMed Scopus (25) Google Scholar, as well as TLR4-associated CD14 and MD-2 proteins (Kollisch et al., 2005Kollisch G. Kalali B.N. Voelcker V. et al.Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes.Immunology. 2005; 114: 531-541Crossref PubMed Scopus (186) Google Scholar in culture and in the skin. In addition, some studies also showed the presence of TLR7, 8, and 9 (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: 1389-1396Crossref PubMed Scopus (171) Google Scholar; Miller et al., 2005Miller L.S. Sorensen O.E. Liu P.T. et al.TGF-alpha regulates TLR expression and function on epidermal keratinocytes.J Immunol. 2005; 174: 6137-6143Crossref PubMed Google Scholar; Flacher et al., 2006Flacher V. Bouschbacher M. Verronese E. et al.Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria.J Immunol. 2006; 177: 7959-7967Crossref PubMed Google Scholar; Lebre et al., 2007Lebre M.C. van der Aar A.M. van Baarsen L. et al.Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.J Invest Dermatol. 2007; 127: 331-341Crossref PubMed Scopus (181) Google Scholar in these cells. Moreover, TLR expression can be further upregulated by certain pathogens, e.g., Mycobacteria (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 (221) Google Scholar; Lee et al., 2009Lee H.M. Shin D.M. Choi D.K. et al.Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes.Cell Microbiol. 2009; 11: 678-692Crossref PubMed Scopus (43) Google Scholar, Malassezzia (Baroni et al., 2006Baroni A. Orlando M. Donnarumma G. et al.Toll-like receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur.Arch Dermatol Res. 2006; 297: 280-288Crossref PubMed Scopus (60) Google Scholar, Propionibacterium (Jugeau et al., 2005Jugeau S. Tenaud I. Knol A.C. et al.Induction of toll-like receptors by Propionibacterium acnes.Br J Dermatol. 2005; 153: 1105-1113Crossref PubMed Scopus (135) Google Scholar, viral stimulation (Lebre et al., 2003Lebre M.C. Antons J.C. Kalinski P. et al.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 (67) Google Scholar; Kalali et al., 2008Kalali B.N. Kollisch G. Mages J. et al.Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling.J Immunol. 2008; 181: 2694-2704Crossref PubMed Google Scholar, and various pathogen-derived products (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 (221) Google Scholar; Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar. Cytokines such as transforming growth factor-α and IFN-α (Miller et al., 2005Miller L.S. Sorensen O.E. Liu P.T. et al.TGF-alpha regulates TLR expression and function on epidermal keratinocytes.J Immunol. 2005; 174: 6137-6143Crossref PubMed Google Scholar; Prens et al., 2008Prens E.P. Kant M. van Dijk G. et al.IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis.J Invest Dermatol. 2008; 128: 932-938Crossref PubMed Scopus (21) Google Scholar also enhance TLR levels in KCs in vitro. In agreement with this, increased expression of certain TLRs has been observed in inflammatory and infectious skin diseases such as psoriasis, acne, atopic eczema, and Varicella–Zoster virus infection (Baker et al., 2003Baker B.S. Ovigne J.M. Powles A.V. et al.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 (174) Google Scholar; Lai and Gallo, 2008Lai Y. Gallo R.L. Toll-like receptors in skin infections and inflammatory diseases.Infect Disord Drug Targets. 2008; 8: 144-155Crossref PubMed Google Scholar. In addition to the TLRs, it has been recently documented that KCs express other receptors that recognize conserved molecular patterns, e.g., NOD-like receptors. Both NOD 1 and 2 seem to be constitutively present in these cells (Harder and Nunez, 2009Harder J. Nunez G. Functional expression of the intracellular pattern recognition receptor NOD1 in human keratinocytes.J Invest Dermatol. 2009; 129: 1299-1302Crossref PubMed Scopus (8) Google Scholar; Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar. NOD1 can be further upregulated under stimulation with cytokines, especially IFN-γ (Harder and Nunez, 2009Harder J. Nunez G. Functional expression of the intracellular pattern recognition receptor NOD1 in human keratinocytes.J Invest Dermatol. 2009; 129: 1299-1302Crossref PubMed Scopus (8) Google Scholar. Relevance of the pathway was additionally demonstrated by detection of IL-8 release from KCs during the response to infection with NOD1-activating bacteria, Pseudomonas aeruginosa (Harder and Nunez, 2009Harder J. Nunez G. Functional expression of the intracellular pattern recognition receptor NOD1 in human keratinocytes.J Invest Dermatol. 2009; 129: 1299-1302Crossref PubMed Scopus (8) Google Scholar. Expression and function of NOD2 receptor in the epidermis was investigated in the context of antimicrobial function by Voss et al., 2006Voss E. Wehkamp J. Wehkamp K. et al.NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2.J Biol Chem. 2006; 281: 2005-2011Crossref PubMed Scopus (205) Google Scholar. This study demonstrated that the activation of the NOD2 pathway results in HBD-2 production (Voss et al., 2006Voss E. Wehkamp J. Wehkamp K. et al.NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2.J Biol Chem. 2006; 281: 2005-2011Crossref PubMed Scopus (205) Google Scholar. On the basis of a murine model, Kim et al., 2008Kim J.Y. Omori E. Matsumoto K. et al.TAK1 is a central mediator of NOD2 signaling in epidermal cells.J Biol Chem. 2008; 283: 137-144Crossref PubMed Scopus (50) Google Scholar suggested that transforming growth factor–activated kinase 1 is an essential signaling molecule in the NOD2 pathway and important for maintenance of epidermal homeostasis (Omori et al., 2006Omori E. Matsumoto K. Sanjo H. et al.TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis.J Biol Chem. 2006; 281: 19610-19617Crossref PubMed Scopus (83) Google Scholar. C-type lectins comprise another group of conserved pattern receptors that may have a role in epidermal recognition of microbes. In the steady state, KCs express low levels or appear negative for the expression of the best-characterized member of this group, dectin-1 (Lee et al., 2009Lee H.M. Shin D.M. Choi D.K. et al.Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes.Cell Microbiol. 2009; 11: 678-692Crossref PubMed Scopus (43) Google Scholar; de Koning et al., 2010de Koning H.D. Rodijk-Olthuis D. van Vlijmen-Willems I.M. et al.A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis.J Invest Dermatol. 2010; 130: 2611-2620Crossref PubMed Scopus (25) Google Scholar. However, the expression of dectin-1 is inducible in KCs on exposure to bacteria and the receptor aids pathogen internalization, as demonstrated in Mycobacterium ulcerans infection (Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar. The same study reported that the stimulation by β-glucan itself can also upregulate its own receptor (Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar, which suggests a possibility that dectin-1 could be induced upon exposure to various fungal species. Very recently, KCs were also tested for the expression of members of the family of RIG-like helicase receptors that are able to detect viral single-stranded RNA and double-stranded RNA (Kalali et al., 2008Kalali B.N. Kollisch G. Mages J. et al.Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling.J Immunol. 2008; 181: 2694-2704Crossref PubMed Google Scholar. Kalali et al., 2008Kalali B.N. Kollisch G. Mages J. et al.Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling.J Immunol. 2008; 181: 2694-2704Crossref PubMed Google Scholar demonstrated that human KCs constitutively express low levels of RIG-I, MDA-5, and protein kinase R and that these virus-sensing receptors can be upregulated by several-fold following exposure to poly I:C. The authors also highlighted the importance of protein kinase R as a central antiviral mechanism for double-stranded RNA stimulation, controlling a broad spectrum of pathways activated during viral invasion (Kalali et al., 2008Kalali B.N. Kollisch G. Mages J. et al.Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling.J Immunol. 2008; 181: 2694-2704Crossref PubMed Google Scholar. Inflammatory conditions are also likely to influence the recognition of double-stranded RNA by RIG-like helicase receptors in KCs, as demonstrated under IFN-γ stimulation (Prens et al., 2008Prens E.P. Kant M. van Dijk G. et al.IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis.J Invest Dermatol. 2008; 128: 932-938Crossref PubMed Scopus (21) Google Scholar. Enhanced expression of molecules belonging to this group of pattern recognition receptors has been reported in various skin conditions (Prens et al., 2008Prens E.P. Kant M. van Dijk G. et al.IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis.J Invest Dermatol. 2008; 128: 932-938Crossref PubMed Scopus (21) Google Scholar; Zahn et al., 2011Zahn S. Barchet W. Rehkamper C. et al.Enhanced skin expression of melanoma differentiation-associated gene 5 (MDA5) in dermatomyositis and related autoimmune diseases.J Am Acad Dermatol. 2011; 64: 988-989Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, which suggests relevance to the inflammatory state. In agreement with this, upregulation of the receptors under IFN-α/γ stimulation in the in vitro model of psoriasis has been reported (Racz et al., 2011Racz E. Prens E.P. Kant M. et al.Narrowband ultraviolet B inhibits innate cytosolic double-stranded RNA receptors in psoriatic skin and keratinocytes.Br J Dermatol. 2011; 164: 838-847Crossref PubMed Scopus (3) Google Scholar. Interestingly, this overexpression was demonstrated to diminish under UVB exposure (Racz et al., 2011Racz E. Prens E.P. Kant M. et al.Narrowband ultraviolet B inhibits innate cytosolic double-stranded RNA receptors in psoriatic skin and keratinocytes.Br J Dermatol. 2011; 164: 838-847Crossref PubMed Scopus (3) Google Scholar, known to dampen the inflammation in psoriatic patients. Finally, the notion of RNF114, recently reported as a novel target gene in psoriasis by genome-wide association studies (Capon et al., 2008Capon F. Bijlmakers M.J. Wolf N. et al.Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.Hum Mol Genet. 2008; 17: 1938-1945Crossref PubMed Scopus (103) Google Scholar, as a regulator of RIG-I/MDA5 signaling in KCs, suggests that these viral sensors are key mediators during epithelial autoimmune inflammation (Bijlmakers et al., 2011Bijlmakers M.J. Kanneganti S.K. Barker J.N. et al.Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis.Hum Mol Genet. 2011; 20 (3): 3129Crossref PubMed Scopus (21) Google Scholar. As shown above, considerable evidence points to the role of KCs in early detection of pathogens characterized by the presence of conserved molecular patterns, such as viral nucleic acids, lipopolysaccharide, flagellin, and zymosan, and so on. Sensing incoming threats enables the epidermis to react as the first line of response that involves, depending on the agonist, induction of chemotactic mediators, such as IL-8, CCL2, CCL20, CCL27, CXCL16, CXCL9, and CXCL10 (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 (221) Google Scholar; Kollisch et al., 2005Kollisch G. Kalali B.N. Voelcker V. et al.Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes.Immunology. 2005; 114: 531-541Crossref PubMed Scopus (186) Google Scholar; Miller et al., 2005Miller L.S. Sorensen O.E. Liu P.T. et al.TGF-alpha regulates TLR expression and function on epidermal keratinocytes.J Immunol. 2005; 174: 6137-6143Crossref PubMed Google Scholar; Lebre et al., 2007Lebre M.C. van der Aar A.M. van Baarsen L. et al.Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.J Invest Dermatol. 2007; 127: 331-341Crossref PubMed Scopus (181) Google Scholar; Tohyama et al., 2007Tohyama M. Sayama K. Komatsuzawa H. et al.CXCL16 is a novel mediator of the innate immunity of epidermal keratinocytes.Int Immunol. 2007; 19: 1095-1102Crossref PubMed Scopus (21) Google Scholar; Lee et al., 2009Lee H.M. Shin D.M. Choi D.K. et al.Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes.Cell Microbiol. 2009; 11: 678-692Crossref PubMed Scopus (43) Google Scholar; Niebuhr et al., 2010Niebuhr M. Baumert K. Werfel T. TLR-2-mediated cytokine and chemokine secretion in human keratinocytes.Exp Dermatol. 2010; 19: 873-877Crossref PubMed Scopus (18) Google Scholar. In addition, proinflammatory tumor necrosis factor (TNF)-α, type I IFN, IL-1α, IL-6, IL-18, defensins, cathelicidin (LL-37), and thymic stromal lymphopoietin (TSLP) secretion can be also observed (Lebre et al., 2007Lebre M.C. van der Aar A.M. van Baarsen L. et al.Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.J Invest Dermatol. 2007; 127: 331-341Crossref PubMed Scopus (181) Google Scholar; Prens et al., 2008Prens E.P. Kant M. van Dijk G. et al.IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis.J Invest Dermatol. 2008; 128: 932-938Crossref PubMed Scopus (21) Google Scholar; Kinoshita et al., 2009Kinoshita H. Takai T. Anh Le T. et al.Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA.J Allergy Clin Immunol. 2009; 123: 179-186Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar; Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar. These key mediators help promote recruitment of neutrophils, monocytes, dendritic cells (DCs), and various subsets of lymphocytes to the epidermis. Several studies have observed links between pathways of innate systems of microbial recognition in KCs. For example, dectin-1 expression can be modulated by TLR2 stimulation (Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar; Lee et al., 2009Lee H.M. Shin D.M. Choi D.K. et al.Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes.Cell Microbiol. 2009; 11: 678-692Crossref PubMed Scopus (43) Google Scholar. Moreover, very recently, Muller-Anstett et al., 2010Muller-Anstett M.A. Muller P. Albrecht T. et al.Staphylococcal peptidoglycan co-localizes with Nod2 and TLR2 and activates innate immune response via both receptors in primary murine keratinocytes.PLoS One. 2010; 5: e13153Crossref PubMed Scopus (33) Google Scholar have also reported that Staphylococcal peptidoglycan is able to stimulate both NOD-2 and TLR2 receptor in mice. These examples indicate that there is a degree of cross-talk between innate pathways in KCs. It has also been reported that levels of TLR2, NOD-2, and dectin-1 are amplified by histamine stimulation (Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (38) Google Scholar. This synergism between pattern recognition receptors and histamine suggests that there could be positive feedback between mechanisms of innate immunity and inflammation, especially during allergic-type responses in the skin. This could potentially result in an increased reactivity to pathogens, e.g., in the skin of atopic individuals. Finally, very intriguing data come from the recent study of Trompette et al., 2009Trompette A. Divanovic S. Visintin A. et al.Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein.Nature. 2009; 457: 585-588Crossref PubMed Scopus (352) Google Scholar, who revealed that apart from structural mimicry between MD-2 molecules and house dust mite antigen Der p2 (Derewenda et al., 2002Derewenda U. Li J. Derewenda Z. et al.The crystal structure of a major dust mite allergen Der p 2, and its biological implications.J Mol Biol. 2002; 318: 189-197Crossref PubMed Scopus (85) Google Scholar; Kim et al., 2007Kim H.M. Park B.S. Kim J. et al.Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.Cell. 2007; 130: 906-917Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar; Ohto et al., 2007Ohto U. Fukase K. Miyake K. et al.Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa.Science. 2007; 316: 1632-1634Crossref PubMed Scopus (250) Google Scholar, there is also a strong functional similarity, resulting in nonspecific adjuvant-like effect of the antigen via innate immune pathways. Taken together, it is clear that KCs are well equipped in mechanisms that support detection of conserved molecules, which can be enhanced further as the cells encounter pathogens. Activation of these pathways results in cytokine and chemokine release, independent from epidermal or dermal immune cells. Moreover, any further interactions between the innate pathways of microbial recognition are likely to additionally enhance the induction of proinflammatory factors, which further supports adjuvant-like properties of the epidermis. This suggests that KCs have an important role during the innate phase of immune responses to invading pathogens as they react by an early wave of chemokine and cytokine release and attract key effector immune cells. Various studies documented that KCs do not normally express the co-stimulatory molecules CD80/86 (Black et al., 2007Black A.P. Ardern-Jones M.R. Kasprowicz V. et al.Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells.Eur J Immunol. 2007; 37: 1485-1493Crossref PubMed Scopus (27) Google Scholar, and thus they are unlikely to prime naïve T cells in a steady state (Gaspari et al., 1988Gaspari A.A. Jenkins M.K. Katz S.I. Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones.J Immunol. 1988; 141: 2216-2220PubMed Google Scholar; Otten et al., 1996Otten H.G. Bor B. Ververs C. et al.Alloantigen-specific T-cell anergy induced by human keratinocytes is abrogated upon loss of cell-cell contact.Immunology. 1996; 88: 214-219Crossref PubMed Google Scholar; Laning et al., 1997Laning J.C. Isaacs C.M. Hardin-Young J. Normal human keratinocytes inhibit the proliferation of unprimed T cells by TGFbeta and PGE2, but not IL-10.Cell Immunol. 1997; 175: 16-24Crossref PubMed Scopus (12) Google Scholar. Consistently, early reports have indicated that class-II–mediated presentation of antigen by KCs results in tolerance or anergy of T cells (Gaspari et al., 1988Gaspari A.A. Jenkins M.K. Katz S.I. Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones.J Immunol. 1988; 141: 2216-2220PubMed Google Scholar; Bal et al., 1990Bal V. McIndoe A. Denton G. et al.Antigen presentation by keratinocytes induces tolerance in human T cells.Eur J Immunol. 1990; 20: 1893-1897Crossref PubMed Google Scholar. However, the upregulation of molecules involved in the stimulation of T cells by KCs has been observed in multiple human skin diseases, which implies that during inflammatory states, KCs may be able to stimulate antigen-experienced T cells. However, most authors agree that they are unlikely to be able to prime new T-cell responses, a characteristic of conventional antigen-presenting cells (APCs) such as DCs. Specifically, it has been demonstrated that under certain inflammatory conditions, KCs can upregulate both major histocompatibility complex class I and II molecules (Basham et al., 1985Basham T.Y. Nickoloff B.J. Merigan T.C. et al.Recombinant gamma interferon differentially regulates class II antigen expression and biosynthesis on cultured normal human keratinocytes.J Interferon Res. 1985; 5: 23-32Crossref PubMed Google Scholar; Bieber et al., 1989Bieber T. Dannenberg B. Ring J. et al.Keratinocytes in lesional skin of atopic eczema bear HLA-DR, CD1a and IgE molecules.Clin Exp Dermatol. 1989; 14: 35-39Crossref PubMed Google Scholar; Banno et al., 2003Banno T. Adachi M. Mukkamala L. et al.Unique keratinocyte-specific effects of interferon-gamma that protect skin from viruses, identified using transcriptional profili" @default.
• W2015336716 created "2016-06-24" @default.
• W2015336716 creator A5013661223 @default.
• W2015336716 creator A5050511886 @default.
• W2015336716 date "2012-03-01" @default.
• W2015336716 modified "2023-09-26" @default.
• W2015336716 title "The Epidermis as an Adjuvant" @default.
• W2015336716 cites W1502004968 @default.
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