The cutaneous innate immune response in patients with atopic dermatitis
2013; Elsevier BV; Volume: 131; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2012.12.1563
ISSN1097-6825
AutoresI‐Hsin Kuo, Takeshi Yoshida, Anna De Benedetto, Lisa A. Beck,
Tópico(s)Allergic Rhinitis and Sensitization
ResumoOrchestrating when and how the cutaneous innate immune system should respond to commensal or pathogenic microbes is a critical function of the epithelium. The cutaneous innate immune system is a key determinant of the physical, chemical, microbial, and immunologic barrier functions of the epidermis. A malfunction in this system can lead to an inadequate host response to a pathogen or a persistent inflammatory state. Atopic dermatitis is the most common inflammatory skin disorder and characterized by abnormalities in both skin barrier structures (stratum corneum and tight junctions), a robust TH2 response to environmental antigens, defects in innate immunity, and an altered microbiome. Many of these abnormalities may occur as the consequence of epidermal dysfunction. The epidermis directly interfaces with the environment and, not surprisingly, expresses many pattern recognition receptors that make it a key player in cutaneous innate immune responses to skin infections and injury. This review will discuss the role epidermal innate receptors play in regulation of skin barriers and, where possible, discuss the relevance of these findings for patients with atopic dermatitis. Orchestrating when and how the cutaneous innate immune system should respond to commensal or pathogenic microbes is a critical function of the epithelium. The cutaneous innate immune system is a key determinant of the physical, chemical, microbial, and immunologic barrier functions of the epidermis. A malfunction in this system can lead to an inadequate host response to a pathogen or a persistent inflammatory state. Atopic dermatitis is the most common inflammatory skin disorder and characterized by abnormalities in both skin barrier structures (stratum corneum and tight junctions), a robust TH2 response to environmental antigens, defects in innate immunity, and an altered microbiome. Many of these abnormalities may occur as the consequence of epidermal dysfunction. The epidermis directly interfaces with the environment and, not surprisingly, expresses many pattern recognition receptors that make it a key player in cutaneous innate immune responses to skin infections and injury. This review will discuss the role epidermal innate receptors play in regulation of skin barriers and, where possible, discuss the relevance of these findings for patients with atopic dermatitis. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: February 2013. Credit may be obtained for these courses until January 31, 2014.Copyright Statement: Copyright © 2013-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: I-Hsin Kuo, MS, Takeshi Yoshida, PhD, Anna De Benedetto, MD, and Lisa A. Beck, MDActivity Objectives1.To recognize the innate immune receptors present in skin.2.To recognize alterations in the innate immune response found in patients with atopic dermatitis.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: I-H. Kuo has received research and travel support from the Atopic Dermatitis Research Network. T. Yoshida has received research support from the Atopic Dermatitis Research Network. A. De Benedetto has received research support from the National Eczema Association and Dermatology Foundation and has received travel support from the Atopic Dermatitis Research Network. L. A. Beck has received research and travel support from the Atopic Dermatitis Research Network, has received research support from Regeneron and Genentech, is on the Society of Investigative Dermatology Board of Directors, and has received consultancy fees from Regeneron. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: February 2013. Credit may be obtained for these courses until January 31, 2014. Copyright Statement: Copyright © 2013-2014. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: I-Hsin Kuo, MS, Takeshi Yoshida, PhD, Anna De Benedetto, MD, and Lisa A. Beck, MD Activity Objectives1.To recognize the innate immune receptors present in skin.2.To recognize alterations in the innate immune response found in patients with atopic dermatitis. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: I-H. Kuo has received research and travel support from the Atopic Dermatitis Research Network. T. Yoshida has received research support from the Atopic Dermatitis Research Network. A. De Benedetto has received research support from the National Eczema Association and Dermatology Foundation and has received travel support from the Atopic Dermatitis Research Network. L. A. Beck has received research and travel support from the Atopic Dermatitis Research Network, has received research support from Regeneron and Genentech, is on the Society of Investigative Dermatology Board of Directors, and has received consultancy fees from Regeneron. Our skin acts as a sentinel, determining when and how to respond to a broad array of environmental insults during both homeostatic and pathologic states. It is quite remarkable that recurrent infections or unchecked inflammatory responses are so infrequent. The decision to either unleash a full assault or covertly deal with the intruder is a tightly orchestrated symphony involving at least 4 epidermal elements. The first of these elements is the physical barrier, which consists of both the stratum corneum (SC), with its brick-and-mortar structure, and the tight junctions (TJs), which are directly below the SC in the stratum granulosum. The second element is the chemical barrier, consisting of a broad range of antimicrobial proteins, including classical antimicrobial peptides (AMPs), S100 family members, and even filaggrin breakdown products. The third element is the skin microbial flora commonly referred to as the microbiome, which consists of many bacterial, fungal, and viral phyla and subphyla. These microorganisms play a key role in the initiation, prevention, or both of skin inflammation and immune responses and protect the host from pathogens such as Staphylococcus aureus. Finally, there is the immunologic barrier, which has an immediate but somewhat nonspecific arm (ie, innate immunity) and a highly specific and long-lasting arm (ie, adaptive immunity). Much of the character of the adaptive immune response (eg, antigen-specific tolerance or recall responses) is determined by the interplay of the innate immune system with the other epidermal elements. For example, a breach in the physical barrier would favor the entry and immunologic recognition of antigens, pathogens, or both, but the character and magnitude of this response will be modulated by the epidermal innate immune response, barrier repair response, and host-microbe micro-environment. Atopic dermatitis (AD) is the most common inflammatory skin disease, affecting up to 15% to 25% of children and 3% of adults in the United States.1Laughter D. Istvan J.A. Tofte S.J. Hanifin J.M. The prevalence of atopic dermatitis in Oregon schoolchildren.J Am Acad Dermatol. 2000; 43: 649-655Abstract Full Text Full Text PDF PubMed Google Scholar, 2Odhiambo J.A. Williams H.C. Clayton T.O. Robertson C.F. Asher M.I. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three.J Allergy Clin Immunol. 2009; 124: 1251-1258.e23Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar Impaired skin barriers, reduced expression of epidermally derived antimicrobial products, TH2-skewed inflammation, a defect in innate receptor functions, and restricted cutaneous microbial diversity are critical biological features observed in the majority of patients with AD. For many years, AD was considered primarily an immunologic disease, but more recently, epithelial barrier dysfunction has emerged as another key feature.3Boguniewicz M. Leung D.Y. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation.Immunol Rev. 2011; 242: 233-246Crossref PubMed Scopus (776) Google Scholar, 4Holgate S.T. Epithelium dysfunction in asthma.J Allergy Clin Immunol. 2007; 120: 1233-1246Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar There is consensus that the leaky epithelial barrier promotes allergen sensitization and susceptibility to microbial colonization and even infections.5Elias P.M. Steinhoff M. Outside-to-inside" (and now back to "outside") pathogenic mechanisms in atopic dermatitis.J Invest Dermatol. 2008; 128: 1067-1070Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 6De Benedetto A. Kubo A. Beck L.A. Skin barrier disruption: a requirement for allergen sensitization?.J Invest Dermatol. 2012; 132: 949-963Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 7Kubo A. Nagao K. Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases.J Clin Invest. 2012; 122: 440-447Crossref PubMed Scopus (255) Google Scholar The controversy emerges when one considers which of these defects initiate the disease. In other words, do barrier defects predate the immune abnormalities or vice versa? Both possibilities can be supported by a number of observational and mechanistic studies. For example, TH2 cytokines found in nonlesional AD skin adversely affect skin barrier protein expression and function and are strongly associated with risk of S aureus colonization or eczema herpeticum.3Boguniewicz M. Leung D.Y. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation.Immunol Rev. 2011; 242: 233-246Crossref PubMed Scopus (776) Google Scholar, 8Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. DeBenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2009; 124: R7-R12Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 9Kim B.E. Leung D.Y. Boguniewicz M. Howell M.D. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6.Clin Immunol. 2008; 126: 332-337Crossref PubMed Scopus (398) Google Scholar, 10Sehra S. Yao Y. Howell M.D. Nguyen E.T. Kansas G.S. Leung D.Y. et al.IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation.J Immunol. 2010; 184: 3186-3190Crossref PubMed Scopus (140) Google Scholar, 11Beck L.A. Boguniewicz M. Hata T. Schneider L.C. Hanifin J. Gallo R. et al.Phenotype of atopic dermatitis subjects with a history of eczema herpeticum.J Allergy Clin Immunol. 2009; 124 (e1-7): 260-269Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar Mice lacking the SC protein filaggrin (ft/ft) are more susceptible to epicutaneous allergen sensitization, but somewhat unexpectedly, the CD4+ T-cell response is mixed (TH17 > TH2 = TH1).12Oyoshi M.K. Murphy G.F. Geha R.S. Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.J Allergy Clin Immunol. 2009; 124: 485-493.e1Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar One wonders whether the relative contribution of these 2 abnormalities will ultimately help explain some of the heterogeneity observed in human subjects with this disease. Possibly this might help us predict the magnitude of allergen sensitization, age of onset, natural history, comorbidities, treatment responses, and susceptibility to cutaneous pathogens to name just a few unexplained variables noted in patients with AD.8Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. DeBenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2009; 124: R7-R12Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 9Kim B.E. Leung D.Y. Boguniewicz M. Howell M.D. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6.Clin Immunol. 2008; 126: 332-337Crossref PubMed Scopus (398) Google Scholar, 10Sehra S. Yao Y. Howell M.D. Nguyen E.T. Kansas G.S. Leung D.Y. et al.IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation.J Immunol. 2010; 184: 3186-3190Crossref PubMed Scopus (140) Google Scholar, 13Howell M.D. Fairchild H.R. Kim B.E. Bin L. Boguniewicz M. Redzic J.S. et al.Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation.J Invest Dermatol. 2008; 128: 2248-2258Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 14Cornelissen C. Marquardt Y. Czaja K. Wenzel J. Frank J. Luscher-Firzlaff J. et al.IL-31 regulates differentiation and filaggrin expression in human organotypic skin models.J Allergy Clin Immunol. 2012; 129 (e1-8): 426-433Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 15Howell M.D. Boguniewicz M. Pastore S. Novak N. Bieber T. Girolomoni G. et al.Mechanism of HBD-3 deficiency in atopic dermatitis.Clin Immunol. 2006; 121: 332-338Crossref PubMed Scopus (160) Google Scholar The innate immune system is a defense strategy used by plants, fungi, invertebrates, and vertebrates that has evolved over millions of years. It provides a rapid and first-line response to pathogens before the host initiates and/or reactivates the adaptive response, which is more specific and has long-lasting memory. Keratinocytes express a number of innate immune receptors collectively referred to as pattern recognition receptors (PRRs) that enable them to respond to microbes or tissue damage by releasing a broad range of inflammatory mediators (eg, cytokines, chemokines, and AMPs). These PRRs can also affect TJ integrity. For example, Toll-like receptor (TLR) 2 agonists enhance the tightness of TJs and arguably limit penetration of surface proteins/microbes.16Yuki T. Yoshida H. Akazawa Y. Komiya A. Sugiyama Y. Inoue S. Activation of TLR2 enhances tight junction barrier in epidermal keratinocytes.J Immunol. 2011; 187: 3230-3237Crossref PubMed Scopus (102) Google Scholar, 17Kuo I.H. Carpenter-Mendini A. Yoshida T. McGirt L.Y. Ivanov A.I. Barnes K.C. et al.Activation of epidermal Toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair.J Invest Dermatol. 2012; ([Epub ahead of print])Google Scholar Therefore a defect in this innate immune-mediated epidermal barrier repair process might lead to chronic inflammation from PRR signaling, as seen in patients with AD who are colonized with S aureus. The innate immune response is also shaped by the skin microbiome and vice versa. The balance between symbiotic and pathogenic microbial populations is determined by the local ecosystem which varies in different anatomical locations for reasons we do not yet understand.18Grice E.A. Segre J.A. The skin microbiome.Nat Rev Microbiol. 2011; 9: 244-253Crossref PubMed Scopus (1992) Google Scholar The epidermal contributions to this ecosystem that determine the local microbiome are areas of active research that hold much promise. An effective innate immune system plays a critical role in orchestrating skin barrier functions, eliciting the proper adaptive immune response, and determining the character of the skin microbiome. Abnormal epithelial homeostasis, reduced AMP production, skewed adaptive immune responses, and changes in the local microbiome, which are known features of AD, could all be due in part to a diminished innate immune response (Fig 1). This review will highlight the importance of epidermal PRRs in AD pathogenesis. We will review what is known about epidermal PRR expression, function, and localization in the skin and how this can affect the 4 other epidermal barriers (the physical barrier, chemical barrier, microbiome, and immunologic barrier). PRRs have been divided into 4 subclasses: TLRs, NOD-like receptors (NLRs), retinoic acid–inducible gene (RIG)–like receptors (RLRs), and C-type lectin receptors (CLRs).19Kumagai Y. Akira S. Identification and functions of pattern-recognition receptors.J Allergy Clin Immunol. 2010; 125: 985-992Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although not included in this classification, peptidoglycan recognition proteins (PGLYRPs) are also recognized as PRRs and are thought to be important for bacterial infections. TLRs are the most extensively studied innate receptors, with 10 identified to date in human subjects. TLRs are transmembrane proteins with a leucine-rich extracellular domain and a highly conserved intracellular signaling domain called the Toll–IL-1 receptor domain. They recognize a wide range of pathogen-associated molecular patterns (PAMPs), including LPS, lipoproteins, flagellin, and lipoteichoic acid (LTA) from bacteria and dsRNA, dsDNA, and unmethylated CpG DNA from bacteria and viruses (Table I).16Yuki T. Yoshida H. Akazawa Y. Komiya A. Sugiyama Y. Inoue S. Activation of TLR2 enhances tight junction barrier in epidermal keratinocytes.J Immunol. 2011; 187: 3230-3237Crossref PubMed Scopus (102) Google Scholar, 19Kumagai Y. Akira S. Identification and functions of pattern-recognition receptors.J Allergy Clin Immunol. 2010; 125: 985-992Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 20Takeuchi O. Akira S. Pattern recognition receptors and inflammation.Cell. 2010; 140: 805-820Abstract Full Text Full Text PDF PubMed Scopus (5976) Google Scholar, 21Kalali B.N. Kollisch G. Mages J. Muller T. Bauer S. Wagner H. 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 Scopus (148) Google Scholar, 22Morizane S. Yamasaki K. Muhleisen B. Kotol P.F. Murakami M. Aoyama Y. et al.Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands.J Invest Dermatol. 2012; 132: 135-143Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 23Salpietro C. Rigoli L. Miraglia Del Giudice M. Cuppari C. Di Bella C. Salpietro A. et al.TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study.Int J Immunopathol Pharmacol. 2011; 24: 33-40Crossref PubMed Scopus (0) Google Scholar, 24Novak N. Yu C.F. Bussmann C. Maintz L. Peng W.M. Hart J. et al.Putative association of a TLR9 promoter polymorphism with atopic eczema.Allergy. 2007; 62: 766-772Crossref PubMed Scopus (153) Google Scholar, 25Niebuhr M. Langnickel J. Sigel S. Werfel T. Dysregulation of CD36 upon TLR-2 stimulation in monocytes from patients with atopic dermatitis and the TLR2 R753Q polymorphism.Exp Dermatol. 2010; 19: e296-e298Crossref PubMed Scopus (0) Google Scholar, 26Mrabet-Dahbi S. Dalpke A.H. Niebuhr M. Frey M. Draing C. Brand S. et al.The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis.J Allergy Clin Immunol. 2008; 121: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 27Ahmad-Nejad P. Mrabet-Dahbi S. Breuer K. Klotz M. Werfel T. Herz U. et al.The Toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype.J Allergy Clin Immunol. 2004; 113: 565-567Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 28Oh D.Y. Schumann R.R. Hamann L. Neumann K. Worm M. Heine G. Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis.Allergy. 2009; 64: 1608-1615Crossref PubMed Scopus (54) Google Scholar, 29Potaczek D.P. Nastalek M. Okumura K. Wojas-Pelc A. Undas A. Nishiyama C. An association of TLR2-16934A >T polymorphism and severity/phenotype of atopic dermatitis.J Eur Acad Dermatol Venereol. 2011; 25: 715-721Crossref PubMed Scopus (42) Google Scholar, 30Voss E. Wehkamp J. Wehkamp K. Stange E.F. Schroder J.M. Harder J. NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2.J Biol Chem. 2006; 281: 2005-2011Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 31Harder J. Nunez G. Functional expression of the intracellular pattern recognition receptor NOD1 in human keratinocytes.J Invest Dermatol. 2009; 129: 1299-1302Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 32Weidinger S. Klopp N. Rummler L. Wagenpfeil S. Novak N. Baurecht H.J. et al.Association of NOD1 polymorphisms with atopic eczema and related phenotypes.J Allergy Clin Immunol. 2005; 116: 177-184Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 33Kabesch M. Peters W. Carr D. Leupold W. Weiland S.K. von Mutius E. Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations.J Allergy Clin Immunol. 2003; 111: 813-817Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 34Macaluso F. Nothnagel M. Parwez Q. Petrasch-Parwez E. Bechara F.G. Epplen J.T. et al.Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis.Exp Dermatol. 2007; 16: 692-698Crossref PubMed Scopus (94) Google Scholar, 35Feldmeyer L. Keller M. Niklaus G. Hohl D. Werner S. Beer H.D. The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes.Curr Biol. 2007; 17: 1140-1145Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 36Dai X. Sayama K. Tohyama M. Shirakata Y. Hanakawa Y. Tokumaru S. et al.Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes.J Allergy Clin Immunol. 2011; 127 (e1-4): 806-814Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 37Hau C.S. Tada Y. Shibata S. Uratsuji H. Asano Y. Sugaya M. et al.High calcium, ATP, and poly(I: C) augment the immune response to beta-glucan in normal human epidermal keratinocytes.J Invest Dermatol. 2011; 131: 2255-2262Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 38Lai Y. Cogen A.L. Radek K.A. Park H.J. Macleod D.T. Leichtle A. et al.Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections.J Invest Dermatol. 2010; 130: 2211-2221Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 39Lai Y. Di Nardo A. Nakatsuji T. Leichtle A. Yang Y. Cogen A.L. et al.Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury.Nat Med. 2009; 15: 1377-1382Crossref PubMed Scopus (545) Google Scholar, 40Jin H. Kumar L. Mathias C. Zurakowski D. Oettgen H. Gorelik L. et al.Toll-like receptor 2 is important for the T(H)1 response to cutaneous sensitization.J Allergy Clin Immunol. 2009; 123: 875-882.e1Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 41Lee H.M. Shin D.M. Choi D.K. Lee Z.W. Kim K.H. Yuk J.M. 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 (64) Google Scholar, 42Yamamoto M. Sato T. Beren J. Verthelyi D. Klinman D.M. The acceleration of wound healing in primates by the local administration of immunostimulatory CpG oligonucleotides.Biomaterials. 2011; 32: 4238-4242Crossref PubMed Scopus (22) Google Scholar, 43Cho K.A. Suh J.W. Lee K.H. Kang J.L. Woo S.Y. IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1beta by keratinocytes via the ROS-NLRP3-caspase-1 pathway.Int Immunol. 2012; 24: 147-158Crossref PubMed Scopus (111) Google Scholar, 44Royet J. Dziarski R. Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defences.Nat Rev Microbiol. 2007; 5: 264-277Crossref PubMed Scopus (316) Google Scholar In addition to exogenous ligands, TLRs also recognize endogenous ligands released in response to tissue damage, which are collectively referred to as danger-associated molecular patterns (DAMPs). For example, fragmented hyaluronic acid and heat shock proteins can trigger TLR2 signaling,45Jiang D. Liang J. Fan J. Yu S. Chen S. Luo Y. et al.Regulation of lung injury and repair by Toll-like receptors and hyaluronan.Nat Med. 2005; 11: 1173-1179Crossref PubMed Scopus (1168) Google Scholar and self-RNA can signal through TLR3.46Bernard J.J. Cowing-Zitron C. Nakatsuji T. Muehleisen B. Muto J. Borkowski A.W. et al.Ultraviolet radiation damages self noncoding RNA and is detected by TLR3.Nat Med. 2012; ([Epub ahead of print])Crossref Scopus (302) Google Scholar Most TLRs signal through a myeloid differentiation primary response gene–88 (MyD88)–dependent pathway, activating nuclear factor κB (NF-κB) and resulting in the production of proinflammatory cytokines. Exceptions are TLR3 and TLR4, which use a MyD88-independent pathway that activates interferon regulatory factor 3 and results in IFN-β gene expression.19Kumagai Y. Akira S. Identification and functions of pattern-recognition receptors.J Allergy Clin Immunol. 2010; 125: 985-992Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Human keratinocytes express functional TLR1, TLR2, TLR3, TLR5, and TLR6,47Lebre M.C. van der Aar A.M. van Baarsen L. van Capel T.M. Schuitemaker J.H. Kapsenberg M.L. et al.Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.J Invest Dermatol. 2007; 127: 331-341Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar, 48de Koning H.D. Rodijk-Olthuis D. van Vlijmen-Willems I.M. Joosten L.A. Netea M.G. Schalkwijk J. 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: 2611-2620Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 49Le T.A. Takai T. Vu A.T. Kinoshita H. Chen X. Ikeda S. et al.Flagellin induces the expression of thymic stromal lymphopoietin in human keratinocytes via toll-like receptor 5.Int Arch Allergy Immunol. 2011; 155: 31-37Crossref PubMed Scopus (48) Google Scholar, 50Kobayashi M. Yoshiki R. Sakabe J. Kabashima K. Nakamura M. Tokura Y. 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 (59) Google Scholar, 51Pivarcsi A. Bodai L. Rethi B. Kenderessy-Szabo A. Koreck A. Szell M. et al.Expression and function of Toll-like receptors 2 and 4 in human keratinocytes.Int Immunol. 2003; 15: 721-730Crossref PubMed Scopus (288) Google Scholar, 52Kawai K. Shimura H. Minagawa M. Ito A. Tomiyama K. Ito M. Expression of functional Toll-like receptor 2 on human epidermal keratinocytes.J Dermatol Sci. 2002; 30: 185-194Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 53Begon 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: 497-506PubMed Google Scholar whereas there is some controversy about the expression of TLR4,52Kawai K. Shimura H. Minagawa M. Ito A. Tomiyama K. Ito M. Expression of functional Toll-like receptor 2 on human epidermal keratinocytes.J Dermatol Sci. 2002; 30: 185-194Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 54Mempel M. Voelcker V. Kollisch G. Plank C. Rad R. Gerhard M. 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 PubM
Referência(s)