REVIEW
The Epidermis as an Adjuvant Danuta Gutowska-Owsiak1 and Graham S. Ogg1 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. Journal of Investigative Dermatology (2012) 132, 940–948; doi:10.1038/ jid.2011.398; published online 5 January 2012
INNATE RECOGNITION MECHANISMS OF KERATINOCYTES (KCs) 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 FcgRI, FcgRII, and FcgRIII (Tigalonowa et al., 1990; Cauza et al., 2002), as well as complement receptors, mannose receptor (Szolnoky et al., 2001), and other molecules that potentially aid internalization such as a5b1 fibronectin–binding integrin (Pellegrini et al., 1992). 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., 2007), Candida albicans (Csato et al., 1986; Szolnoky et al., 2001), and Herpes simplex virus (Nicola et al., 2005). In addition, KCs express a spectrum of innate recognition receptors that can screen the external 1
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Correspondence: Graham S. Ogg, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK. E-mail:
[email protected] Abbreviations: DC, dendritic cell; KC, keratinocyte; LC, Langerhans cell; NK, natural killer; TLR, Toll-like receptor; Treg, T-regulatory cell; TSLP, thymic stromal lymphopoietin.
Received 2 July 2011; revised 14 October 2011; accepted 24 October 2011; published online 5 January 2012
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environment and provide proinflammatory and chemotactic signals to immune cells in a case of pathogen invasion. Various studies have reported that KCs also express Tolllike receptors (TLRs) 1–6 and 10 (Baker et al., 2003; Mempel et al., 2003; Pivarcsi et al., 2003, 2004; Flacher et al., 2006; Lebre et al., 2007; de Koning et al., 2010), as well as TLR4associated CD14 and MD-2 proteins (Kollisch et al., 2005) in culture and in the skin. In addition, some studies also showed the presence of TLR7, 8, and 9 (Mempel et al., 2003; Miller et al., 2005; Flacher et al., 2006; Lebre et al., 2007) in these cells. Moreover, TLR expression can be further upregulated by certain pathogens, e.g., Mycobacteria (Pivarcsi et al., 2003; Lee et al., 2009), Malassezzia (Baroni et al., 2006), Propionibacterium (Jugeau et al., 2005), viral stimulation (Lebre et al., 2003; Kalali et al., 2008), and various pathogenderived products (Pivarcsi et al., 2003; Kobayashi et al., 2009). Cytokines such as transforming growth factor-a and IFN-a (Miller et al., 2005; Prens et al., 2008) 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., 2003; Lai and Gallo, 2008). 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, 2009; Kobayashi et al., 2009). NOD1 can be further upregulated under stimulation with cytokines, especially IFN-g (Harder and Nunez, 2009). 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, 2009). Expression and function of NOD2 receptor in the epidermis was investigated in the context of antimicrobial function by Voss et al. (2006). This study demonstrated that the activation of the NOD2 pathway results in HBD-2 production (Voss et al., 2006). On the basis of a murine model, Kim et al. (2008) 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., 2006). 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 bestcharacterized member of this group, dectin-1 (Lee et al., 2009; de Koning et al., 2010). However, the expression of dectin-1 is inducible in KCs on exposure to bacteria and the receptor aids pathogen internalization, as demonstrated in & 2012 The Society for Investigative Dermatology
D Gutowska-Owsiak and GS Ogg Role of Keratinocytes
Mycobacterium ulcerans infection (Kobayashi et al., 2009). The same study reported that the stimulation by b-glucan itself can also upregulate its own receptor (Kobayashi et al., 2009), 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., 2008). Kalali et al. (2008) 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., 2008). Inflammatory conditions are also likely to influence the recognition of double-stranded RNA by RIG-like helicase receptors in KCs, as demonstrated under IFN-g stimulation (Prens et al., 2008). Enhanced expression of molecules belonging to this group of pattern recognition receptors has been reported in various skin conditions (Prens et al., 2008; Zahn et al., 2011), which suggests relevance to the inflammatory state. In agreement with this, upregulation of the receptors under IFN-a/g stimulation in the in vitro model of psoriasis has been reported (Racz et al., 2011). Interestingly, this overexpression was demonstrated to diminish under UVB exposure (Racz et al., 2011), 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., 2008), 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., 2011). 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., 2003; Kollisch et al., 2005; Miller et al., 2005; Lebre et al., 2007; Tohyama et al., 2007; Lee et al., 2009; Niebuhr et al., 2010). In addition, proinflammatory tumor necrosis factor (TNF)-a, type I IFN, IL-1a, IL-6, IL-18, defensins, cathelicidin (LL-37), and thymic stromal lymphopoietin (TSLP) secretion can be also observed (Lebre et al., 2007; Prens et al., 2008; Kinoshita et al., 2009; Kobayashi et al., 2009). 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., 2009; Lee et al., 2009). Moreover, very recently, Muller-Anstett et al. (2010) have also reported that
Staphylococcal peptidoglycan is able to stimulate both NOD2 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., 2009). 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. (2009), who revealed that apart from structural mimicry between MD-2 molecules and house dust mite antigen Der p2 (Derewenda et al., 2002; Kim et al., 2007; Ohto et al., 2007), 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. DIRECT ACTIVATION OF ANTIGEN-SPECIFIC T CELLS Various studies documented that KCs do not normally express the co-stimulatory molecules CD80/86 (Black et al., 2007), and thus they are unlikely to prime naı¨ve T cells in a steady state (Gaspari et al., 1988; Otten et al., 1996; Laning et al., 1997). Consistently, early reports have indicated that classII–mediated presentation of antigen by KCs results in tolerance or anergy of T cells (Gaspari et al., 1988; Bal et al., 1990). 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., 1985; Bieber et al., 1989; Banno et al., 2003; Wittmann et al., 2005; Ardern-Jones et al., 2007), as well as various molecules required for effective major histocompatibility complex peptide loading (Albanesi et al., 1998). In addition, IL-4 exposure has been described to induce co-stimulatory molecules (Junghans et al., 1996), whereas stimulation with IFN-g and, to a lower extent TNF-a, www.jidonline.org
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promotes ICAM-1 expression (Little et al., 1998; Ardern-Jones et al., 2007; Black et al., 2007). The upregulation of ICAM-1 has been also observed when KCs were exposed to some sensitizing agents and oxidative stress (Little et al., 1998). ICAM-1 seems to be able to provide important co-stimulation (Gaglia et al., 2000). In agreement with this, KCs pretreated with IFN-g can efficiently stimulate CD4 þ antigen–specific T cells that have already encountered their cognate antigen (Mutis et al., 1993; Ardern-Jones et al., 2007; Black et al., 2007). Interestingly, Goodman et al. (1994) determined differences in cytokine secretion patterns between T cells stimulated by IFN-g–exposed KCs or peripheral blood mononuclear cells. These data demonstrated that when KCs are involved in stimulating T cells, a bias toward differential T-helper effector function can be observed. Lebre et al. (2007) reported that TLR stimulation of KCs extends further than the release of inflammatory mediators and attracting immune cells to the site of infection. According to this study, TLR ligands, namely poly I:C, flagellin, and lipopolysaccharide, can additionally upregulate expression of class I and class II major histocompatibility complex molecules, along with ICAM-1 and CD40, on KCs (Lebre et al., 2007). This further suggests the possibility of direct interaction of KCs and T cells during adaptive phase of immune response to common pathogens. The mechanisms that allow KCs to directly stimulate T cells have been investigated in the context of S. aureus exposure (Strange et al., 1994; Ardern-Jones et al., 2007). Although only a small percentage of the general population has been reported to be either colonized or infected by the bacteria, the prevalence increases to up to 90% in patients suffering from atopic skin disease (Goh et al., 1997; Chiu et al., 2009; Gomes et al., 2011). First, Strange et al. (1994) observed KC-mediated activation of allogeneic T cells in the presence of IFN-g and staphylo–enterotoxin B that was reduced by the addition of HLA-DR antibodies. However, as staphylo–enterotoxin B represents nonspecific superantigen-type reactivity, relevance of this finding to specific antigen-driven activation was difficult to assess. This problem has been subsequently resolved by Ardern-Jones et al. (2007). In this experimental system, KC-mediated presentation of house dust mite antigen Der p1 to specific CD4 þ T cells significantly increased when the cells were first pretreated with supernatant of staphylo–enterotoxin B–exposed peripheral blood mononuclear cell cultures (Ardern-Jones et al., 2007). The study showed that soluble factors (particularly IFN-g), released from immune cells following exposure to the bacteria, could greatly enhance the T-cell stimulation capabilities of KCs and result in adaptive immune responses to unrelated antigens (including allergens). Although this feature of KCs has only been documented in the context of S. aureus infection, it is plausible that the exposure to other species of either commensal or pathogenic flora could result in a similar switch of antigen-presenting function by KCs. In addition, it is possible that direct or indirect effects of KCs on regulatory T-cell induction or function may be important in influencing the eventual inflammatory milieu, but this has been relatively understudied (Figure 1). 942
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UVB
Pathogens Allergens
Barrier disruption
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Mast cells, NK cells, others
? Nuocytes
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Figure 1. Direct and indirect effects of keratinocytes on innate and adaptive immune responses. DC, dendritic cell; LC, Langerhans cell; NK, natural killer; Treg, T-regulatory cell; TSLP, thymic stromal lymphopoietin.
NONCLASSICAL PRESENTATION BY KCs Apart from involvement in the classical presentation of peptides, KCs could also be capable of facilitating nonclassical pathways, such as presentation of glycolipids via CD1 molecules. The expression of CD1d in normal skin is largely limited to cells of the upper epidermal layers and hair follicle (Bonish et al., 2000; Adly et al., 2005; Fishelevich et al., 2006). However, CD1d is overexpressed (Bonish et al., 2000; Zhao et al., 2008) and can also be present in lower strata in psoriatic skin, which seems to correspond to the observed in vitro effect of IFN-g on its expression (Bonish et al., 2000). Bonish et al. (2000) have also documented that CD1d could be induced in normal KCs by mechanical trauma (tape stripping) and, interestingly, by exposure to poison ivy. CD1d-expressing cultured KCs are able to activate natural killer T cells for cytokine release in vitro, particularly when exposed to IFN-g. This indicates that these cells are potentially capable of presentation of lipid-derived ligands, in the context of both infection and autoimmune inflammation. In contrast, however, despite close proximity, KCs were not able to directly stimulate natural killer T cells during allergic contact dermatitis (Gober et al., 2008). Keratinocytes of the stratified epidermis were also demonstrated to express CD1a, especially in suprabasal regions of atopic skin (Bieber et al., 1989; Furue et al., 1992), but it is not clear whether this represents de novo KC synthesis or acquisition of CD1a from neighboring Langerhans cells. Interestingly, this molecule seems to be a potential target for the newly reported Th22 cells that express a
D Gutowska-Owsiak and GS Ogg Role of Keratinocytes
skin-homing phenotype (Duhen et al., 2009). Although it has been shown that this population is able to respond to the CD1a-mediated presentation by DCs (de Jong et al., 2010), whether these KCs are also able to activate/prime this population remains currently unknown. The expression and functional relevance of stress-induced HLA-related antigens have not been extensively studied in the epidermis. Reports showed that MICA is expressed by human KCs (Zwirner et al., 1998, 1999). In a small study, Molinero et al. (2003) has documented that the expression of this molecule is increased in seborrheic dermatitis. Interestingly, the genetic association with MICA locus has been identified in psoriasis (Zwirner et al., 1998; Romphruk et al., 2004; Pollock et al., 2011). Although these studies suggest an involvement of the molecule in inflammatory process in the skin, the cellular contribution has not yet been identified. KCs CAN INDIRECTLY INFLUENCE IMMUNE RESPONSES Apart from any direct induction of T-cell effector function, activated KCs seem to be also involved in the generation of adaptive responses by affecting APCs in the skin. Initial suggestions that these cells may indeed have a role in the process came from the study by Pastore et al. (1997), who documented the promoting influence of KC-derived GM-CSF on the differentiation of monocytes into DCs and their ability to stimulate naı¨ve T cells. There are some conflicting data regarding the effect of house dust mite antigens on the induction of GM-CSF and IL-8. One study suggested that in contrast to cells of bronchial epithelium, KCs do not express these cytokines (Mascia et al., 2002). However, the release of GM-CSF from KCs has been observed following exposure to Der p1 and Der f1 antigens (Ogawa et al., 2008). Activation of pattern recognition pathways due to stimulation with bacterial products results in the induction of chemokines and cytokines in KCs, as mentioned earlier in this review. In addition, synthesis of the inflammatory derivatives of arachidonic acid is also increased (Eberhard et al., 2002). Exposure of KCs to various Malassezia species also induces a broad spectrum of mediators, including proinflammatory, Th2- and Th17-promoting cytokines (Watanabe et al., 2001; Ishibashi et al., 2006, 2011; Thomas et al., 2008); the profile of response varies depending on the species. Interestingly, the direct interaction involving contact of KCs and fungal cells is required, as Malassezia culture supernatant did not mediate the effect (Watanabe et al., 2001). Moreover, the secretion seems to be enhanced if the yeast is decapsulated (Thomas et al., 2008). Although IL-1a is constitutively produced by KCs (Luger et al., 1981; Sauder et al., 1982; Kupper et al., 1986; Little et al., 1998), it can be further upregulated in response to colonization with Malassezia or bacterial species: Staphylococcus and Propionibacterium (Walters et al., 1995), as well as following epidermal barrier disruption (Wood et al., 1996). Early reports suggested that IL-1a represents the majority or all of IL-1 activity derived from KCs owing to the inability of these cells to effectively process pro-IL-1b into the active form (Kupper et al., 1986; Cooper et al., 1990;
McKenzie et al., 1990; Mizutani et al., 1991). However, others reported the release of IL-1b form by these cells (Watanabe et al., 2001). The functional effects of IL-1 in the skin are broad as many cell types express IL-1 receptors. For example, murine models imply that IL-1a modulates class II expression and function of Langerhans’ cells (Lundqvist and Back, 1990). In addition, overexpression of IL-1a in the epidermis seems to have a significant effect on the recruitment of immune cells, as well as enhancing both T-cell and antibody responses to vaccinia virus (Tian et al., 2008). Moreover, it has been also reported that the epicutaneous sensitization in animal model of contact hypersensitivity is largely dependent on this cytokine, which is required for the activation of contact allergen–specific T cells (Nakae et al., 2001). Keratinocytes also express TNF-a, which seems to be further induced by exposure to lipopolysaccharide (Kock et al., 1990) and UVB (Kock et al., 1990; Schwarz et al., 1995). Early murine studies by Kimber and Cumberbatch, (1992) reported the effect of TNF-a on induction of Langerhans cell migration and their accumulation in the lymph nodes (Cumberbatch and Kimber, 1995). This was also confirmed later by Stoitzner et al. (1999) who detected similar augmentation of the migratory properties in both Langerhans and dermal DCs. More recently, this cytokine has been reported to be involved in the generation of immature Langerhans’ cells from CD34 þ precursors (Arrighi et al., 2003). The role of the cytokine during inflammatory process in the skin has been well documented (Kristensen et al., 1993; Ettehadi et al., 1994; Junghans et al., 1998; Kerstan et al., 2011) and further supported by clinical effectiveness of the anti-TNF treatment in psoriasis (Leonardi et al., 2003; Papp et al., 2005; Marble et al., 2007; Tyring et al., 2007; van de Kerkhof et al., 2008). In 2003, Lebre et al. (2003) investigated the indirect influence of KCs on DC maturation and T-cell polarization in the context of antiviral responses. The study showed that KCs that sense the presence of viral products are able to induce DC maturation in a TNF-a/IL-1b–dependent mode (Lebre et al., 2003). Furthermore, they have also documented that virally activated KCs acquire the ability to indirectly influence the function of activated T cells. Specifically, the presence of type I IFNs and IL-18 in the supernatants from cultures of double-stranded RNA-stimulated KCs influenced IL-12p70 secretion from immature DCs, which in turn induced strong Th1 bias in T cells during their priming (Lebre et al., 2003). A study by Soumelis et al. (2002) showed that TSLP exerts multiple effects on peripheral blood–isolated DCs during their activation and maturation, as well as promotes their survival. Specifically, under TSLP stimulation, DCs produced high levels of CCL17 (TARC) and CCL22 that attract CCR4expressing Th2 cells to the site of inflammation. Interestingly, T cells that were primed by TSLP-stimulated DCs produce a distinct spectrum of cytokines characterized by Th2 bias (including IL-13, IL-5 and IL-4) and increased TNF-a levels. In contrast, this type of stimulation resulted in a reduced release of Th1/Th1-promoting cytokines: IFN-g, IL-12p70, as well as IL-1b and the regulatory IL-10 (Soumelis et al., 2002). As the www.jidonline.org
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authors observed high expression of TSLP in KCs, particularly in atopic dermatitis, as well as in activated mast cells, these findings are particularly relevant to the Th2-type responses in allergic skin inflammation. Subsequently, additional groups have reported findings that support the role of KC-derived TSLP as a Th2-promoting cytokine in the skin. Ito et al. (2005) determined a critical role of OX40 ligation in the TSLP-mediated instructing of T cells to become Th2 committed. Subsequently, Wang et al. (2006) published a study that suggested that TSLP-stimulated bloodderived DCs are involved in inducing Th2 bias not only during priming of naı¨ve cells but also during the maintenance phase of central memory cells and further T-cell polarization. In the following year, Ebner et al. (2007) brought the context directly to the skin when they investigated the effects of the cytokine on freshly isolated Langerhans cells and reported very similar findings; Langerhans cell survival, proliferation, and maturation were enhanced under the stimulation. In addition, the profile of secreted cytokines was parallel to those that Soumelis et al. (2002) observed for the peripheral blood DCs, which suggests that the effect of TSLP is not limited to a given antigen-presenting subset in the blood, but that potentially also APCs in the skin can induce Th2-skewed polarization of naı¨ve T cells. As an additional finding, Ebner et al. (2007) also presented direct evidence implying enhanced migratory properties of Langerhans cells under TSLP stimulation. However, TSLP-mediated impact on innate cells has also been recognized. The study published by Allakhverdi et al. (2007) determined its role in direct activation and induction of proinflammatory and Th2 cytokines, as well as in the release of chemokines from mast cells. The magnitude of the adaptive responses in the skin is also likely to be altered by the milieu that influences KCs. Indeed, this was shown a few years later by Kinoshita et al. (2009) who studied the effect of various cytokines on the TLSP release from KCs following TLR3 stimulation. This study demonstrated an enhancing effect of IL-4, IL-13, type I IFNs, and TNF-a, as well as a downregulating influence of IFN-g, transforming growth factor-b, or IL-17 on the expression and release of this cytokine. Moreover, the integrity of the epidermis seems to be an important factor in the induction of TSLP under TLR3 stimulation as well, as recently documented by Lee et al. (2011) in a filaggrin knockdown model of viral infection. These two studies imply an existence of a positive feedback loop between viral infections and compromised integrity of epidermal barrier on one side and allergic skin inflammation on the other. Another epidermis-derived cytokine that seems to influence antigen-specific adaptive responses is a recently characterized member of the IL-17 family, IL-25 (IL-17E). Keratinocytes have been shown to constitutively express IL25 transcript and protein (Wang et al., 2007; Corrigan et al., 2011). It has been documented in animal studies that stimulation with the cytokine also results in the promotion of Th2 responses (Fort et al., 2001; Pan et al., 2001; Angkasekwinai et al., 2007). Recently, it has been proposed that it is an indirect mechanism and that the cytokine functions by enhancing the Th2 responses driven by TSLP944
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stimulated APCs (Wang et al., 2007), a possible explanation of the induction of the cytokine bias observed in mice. Finally, a novel IL-1-like cytokine, the ‘‘alarmin’’ IL-33, has been detected as a constitutively expressed product present in KCs (Moussion et al., 2008) and upregulated in atopic and psoriatic plaques. The cytokine also seems to have similar functional properties as it seems to promote mainly proinflammatory and Th2-type responses from a spectrum of various cell populations, including antigen-specific–committed Th2 cells (Schmitz et al., 2005; Smithgall et al., 2008). Moreover, it promotes survival of mast cells and, interestingly, their activation independent of IgE cross-linking (Iikura et al., 2007; Hueber et al., 2011). It is also plausible that the aforementioned cytokines also directly affect APCs in the skin, as well as other cells including nuocytes, a novel population of immune cells that seems to respond to IL-25 and IL-33 stimulation by secretion of Th2 cytokines (Neill et al., 2010). These possibilities, however, remain to be formally proven. Keratinocytes are also capable of directing the response toward a Th1-type bias, by inducing IFN-g release from T cells, monocytes and macrophages. For example, IL-18, also constitutively expressed by KCs of the basal epidermal layer and upregulated in psoriatic skin possesses this property (Kohka et al., 1998; Naik et al., 1999). Moreover, the cytokine has been reported to influence Langerhans cell migration in mouse models of contact hypersensitivity (Cumberbatch et al., 2001; Plitz et al., 2003). Taken together, these findings suggest that KCs are a potent source of cytokines that target immune cells, leading to the amplification of local innate and adaptive inflammatory responses. IMPLICATIONS FOR VACCINE DEVELOPMENT As discussed above, KCs are not just bystanders, but immunologically active cells that are able to participate at various stages of the immune response. In fact, the properties of the epidermis described above, including an ability to augment inflammatory state and modify its direction, are also the properties that are characteristics of adjuvants. This carries some important implications for the generation of vaccination strategies, especially regarding the feasibility of relatively recently proposed transcutaneous immunization. Differential antigen delivery can significantly influence the resultant immune response (Estcourt et al., 2005). Human studies documented that immunogenicity against enterotoxigenic strains of Escherichia coli (Glenn et al., 2000, 2007; Guerena-Burgueno et al., 2002; Yu et al., 2002; Frech et al., 2008), flu (Van Kampen et al., 2005), and measles (Etchart et al., 2007) could be induced by transcutaneous immunization. In murine models, efficacy has been reported against tetanus (Shi et al., 2001; Ishii et al., 2008; Matsuo et al., 2011), diphtheria (Matsuo et al., 2011), Japanese encephalitis virus (Cheng et al., 2009), adenovirus (Ishii et al., 2008) and various flu strains (Guebre-Xabier et al., 2004; Garg et al., 2007; Mkrtichyan et al., 2008). The efficacy in inducing systemic humoral and cellular responses has been proven (Guerena-Burgueno et al., 2002;
D Gutowska-Owsiak and GS Ogg Role of Keratinocytes
Yu et al., 2002; Matsuo et al., 2011). In addition, delivery of antigens via such a formulation has been shown to enhance Langerhans cell migration to the draining lymph nodes (Ishii et al., 2008). Specific-IgG titers seem to correlate with measured transepidermal water loss after barrier-disrupting treatment preceding application of the patch (Glenn et al., 2007). Although one can argue that this is a result of increased absorption of active vaccine constituents (antigens, pharmaceutical adjuvants) through the epidermis into dermal layer, it can also be related to the enhanced antigen presentation and secretory capacity of mechanically stimulated KCs. GuebreXabier et al. (2003) have defined a synergistic role of a transepidermal patch (used as an immunostimulant) and subcutaneous injection in mice. This was also reproduced in a human influenza trial in elderly patients (Frech et al., 2005). It is difficult to assess how much of the in vivo systemic effect induced by the patches in the aforementioned studies is due to the adjuvant role of KCs as compared with other cells of the skin. An intriguing study has been also recently published by Liu et al. (2010). The authors of this work aimed to compare the immunogenicity of an antigen administered through the superficially injured skin (skin scarification) with other commonly used delivery routes. Interestingly, they have observed superior efficacy of this method of administration in the induction of both T- and B-cell responses to poxviruses, as well as in the cutaneous melanoma challenge in mice. Certainly, as KCs have the ability to potentiate stimulation of inflammatory pathways, the epidermis could contribute to the modulation of the observed responses, supporting its adjuvant role. In summary, the epidermis is a rich source of cytokines and chemokines that can influence the innate and adaptive immune responses. It is clear that KCs can directly interact with immune cells and indirectly influence function through effects on cutaneous DCs. The underlying mechanisms will be important in understanding disease pathogenesis, as well as informing new approaches for antigen delivery through the skin for vaccination or therapy. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS We are grateful for funding from the MRC and the NIHR Biomedical Research Centre Programme.
Ardern-Jones MR, Black AP, Bateman EA et al. (2007) Bacterial superantigen facilitates epithelial presentation of allergen to T helper 2 cells. Proc Natl Acad Sci USA 104:5557–62 Arrighi JF, Soulas C, Hauser C et al. (2003) TNF-alpha induces the generation of Langerin/(CD207)+ immature Langerhans-type dendritic cells from both CD14-CD1a and CD14+CD1a- precursors derived from CD34+ cord blood cells. Eur J Immunol 33:2053–63 Baker BS, Ovigne JM, Powles AV et al. (2003) Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 148:670–9 Bal V, McIndoe A, Denton G et al. (1990) Antigen presentation by keratinocytes induces tolerance in human T cells. Eur J Immunol 20: 1893–7 Banno T, Adachi M, Mukkamala L et al. (2003) Unique keratinocyte-specific effects of interferon-gamma that protect skin from viruses, identified using transcriptional profiling. Antivir Ther 8:541–54 Baroni A, Orlando M, Donnarumma G et al. (2006) Toll-like receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur. Arch Dermatol Res 297:280–8 Basham TY, Nickoloff BJ, Merigan TC et al. (1985) Recombinant gamma interferon differentially regulates class II antigen expression and biosynthesis on cultured normal human keratinocytes. J Interferon Res 5:23–32 Bieber T, Dannenberg B, Ring J et al. (1989) Keratinocytes in lesional skin of atopic eczema bear HLA-DR, CD1a and IgE molecules. Clin Exp Dermatol 14:35–9 Bijlmakers MJ, Kanneganti SK, Barker JN et al. (2011) Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis. Hum Mol Genet 20:3129–3 Black AP, Ardern-Jones MR, Kasprowicz V et al. (2007) Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells. Eur J Immunol 37:1485–93 Bonish B, Jullien D, Dutronc Y et al. (2000) Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells. J Immunol 165:4076–85 Capon F, Bijlmakers MJ, Wolf N et al. (2008) Identification of ZNF313/ RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet 17:1938–45 Cauza K, Grassauer A, Hinterhuber G et al. (2002) FcgammaRIII expression on cultured human keratinocytes and upregulation by interferon-gamma. J Invest Dermatol 119:1074–9 Cheng JY, Huang HN, Tseng WC et al. (2009) Transcutaneous immunization by lipoplex-patch based DNA vaccines is effective vaccination against Japanese encephalitis virus infection. J Control Release 135: 242–9 Chiu LS, Ho MS, Hsu LY et al. (2009) Prevalence and molecular characteristics of Staphylococcus aureus isolates colonizing patients with atopic dermatitis and their close contacts in Singapore. Br J Dermatol 160:965–71 Cooper KD, Hammerberg C, Baadsgaard O et al. (1990) IL-1 activity is reduced in psoriatic skin. Decreased IL-1 alpha and increased nonfunctional IL-1 beta. J Immunol 144:4593–603
REFERENCES
Corrigan CJ, Wang W, Meng Q et al. (2011) Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses. J Allergy Clin Immunol 128:116–24
Adly MA, Assaf HA, Hussein M (2005) Expression of CD1d in human scalp skin and hair follicles: hair cycle related alterations. J Clin Pathol 58:1278–82
Csato M, Bozoky B, Hunyadi J et al. (1986) Candida albicans phagocytosis by separated human epidermal cells. Arch Dermatol Res 279:136–9
Albanesi C, Cavani A, Girolomoni G (1998) Interferon-gamma-stimulated human keratinocytes express the genes necessary for the production of peptide-loaded MHC class II molecules. J Invest Dermatol 110:138–42
Cumberbatch M, Dearman RJ, Antonopoulos C et al. (2001) Interleukin (IL)18 induces Langerhans cell migration by a tumour necrosis factor-alphaand IL-1beta-dependent mechanism. Immunology 102:323–30
Allakhverdi Z, Comeau MR, Jessup HK et al. (2007) Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 204:253–8
Cumberbatch M, Kimber I (1995) Tumour necrosis factor-alpha is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization. Immunology 84:31–5
Angkasekwinai P, Park H, Wang YH et al. (2007) Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med 204:1509–17
de Jong A, Pena-Cruz V, Cheng TY et al. (2010) CD1a-autoreactive T cells are a normal component of the human alphabeta T cell repertoire. Nat Immunol 11:1102–9
www.jidonline.org
945
D Gutowska-Owsiak and GS Ogg Role of Keratinocytes
de Koning HD, Rodijk-Olthuis D, van Vlijmen-Willems IM et al. (2010) A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis. J Invest Dermatol 130:2611–20 Derewenda U, Li J, Derewenda Z et al. (2002) The crystal structure of a major dust mite allergen Der p 2, and its biological implications. J Mol Biol 318:189–97 Duhen T, Geiger R, Jarrossay D et al. (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10:857–63
Goodman RE, Nestle F, Naidu YM et al. (1994) Keratinocyte-derived T cell costimulation induces preferential production of IL-2 and IL-4 but not IFN-gamma. J Immunol 152:5189–98 Guebre-Xabier M, Hammond SA, Ellingsworth LR et al. (2004) Immunostimulant patch enhances immune responses to influenza virus vaccine in aged mice. J Virol 78:7610–8
Eberhard J, Jepsen S, Pohl L et al. (2002) Bacterial challenge stimulates formation of arachidonic acid metabolites by human keratinocytes and neutrophils in vitro. Clin Diagn Lab Immunol 9:132–7
Guebre-Xabier M, Hammond SA, Epperson DE et al. (2003) Immunostimulant patch containing heat-labile enterotoxin from Escherichia coli enhances immune responses to injected influenza virus vaccine through activation of skin dendritic cells. J Virol 77:5218–25
Ebner S, Nguyen VA, Forstner M et al. (2007) Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigenpresenting cells that induce proallergic T cells. J Allergy Clin Immunol 119:982–90
Guerena-Burgueno F, Hall ER, Taylor DN et al. (2002) Safety and immunogenicity of a prototype enterotoxigenic Escherichia coli vaccine administered transcutaneously. Infect Immun 70:1874–80
Estcourt MJ, Letourneau S, McMichael AJ et al. (2005) Vaccine route, dose and type of delivery vector determine patterns of primary CD8+ T cell responses. Eur J Immunol 35:2532–40 Etchart N, Hennino A, Friede M et al. (2007) Safety and efficacy of transcutaneous vaccination using a patch with the live-attenuated measles vaccine in humans. Vaccine 25:6891–9 Ettehadi P, Greaves MW, Wallach D et al. (1994) Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 96:146–51 Fishelevich R, Malanina A, Luzina I et al. (2006) Ceramide-dependent regulation of human epidermal keratinocyte CD1d expression during terminal differentiation. J Immunol 176:2590–9 Flacher V, Bouschbacher M, Verronese E et al. (2006) Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria. J Immunol 177:7959–67
Harder J, Nunez G (2009) Functional expression of the intracellular pattern recognition receptor NOD1 in human keratinocytes. J Invest Dermatol 129:1299–302 Hueber AJ, Alves-Filho JC, Asquith DL et al. (2011) IL-33 induces skin inflammation with mast cell and neutrophil activation. Eur J Immunol 41:2229–37 Iikura M, Suto H, Kajiwara N et al. (2007) IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Invest 87:971–8 Ishibashi Y, Sugawara K, Sugita T et al. (2011) Secretion of thymic stromal lymphopoietin from human keratinocytes in response to Malassezia yeasts. J Dermatol Sci 62:134–8 Ishibashi Y, Sugita T, Nishikawa A (2006) Cytokine secretion profile of human keratinocytes exposed to Malassezia yeasts. FEMS Immunol Med Microbiol 48:400–9
Fort MM, Cheung J, Yen D et al. (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–95
Ishii Y, Nakae T, Sakamoto F et al. (2008) A transcutaneous vaccination system using a hydrogel patch for viral and bacterial infection. J Control Release 131:113–20
Frech SA, Dupont HL, Bourgeois AL et al. (2008) Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 371:2019–25
Ito T, Wang YH, Duramad O et al. (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202:1213–23
Frech SA, Kenney RT, Spyr CA (2005) Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch. Vaccine 23:946–50 Furue M, Nindl M, Kawabe K et al. (1992) Epitopes for CD1a, CD1b, and CD1c antigens are differentially mapped on Langerhans cells, dermal dendritic cells, keratinocytes, and basement membrane zone in human skin. J Am Acad Dermatol 27:419–26 Gaglia JL, Greenfield EA, Mattoo A et al. (2000) Intercellular adhesion molecule 1 is critical for activation of CD28-deficient T cells. J Immunol 165:6091–8 Garg S, Hoelscher M, Belser JA et al. (2007) Needle-free skin patch delivery of a vaccine for a potentially pandemic influenza virus provides protection against lethal challenge in mice. Clin Vaccine Immunol 14:926–8 Gaspari AA, Jenkins MK, Katz SI (1988) Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones. J Immunol 141:2216–20 Glenn GM, Taylor DN, Li X et al. (2000) Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nat Med 6: 1403–6 Glenn GM, Villar CP, Flyer DC et al. (2007) Safety and immunogenicity of an enterotoxigenic Escherichia coli vaccine patch containing heat-labile toxin: use of skin pretreatment to disrupt the stratum corneum. Infect Immun 75:2163–70
946
Gomes PL, Malavige GN, Fernando N et al. (2011) Characteristics of Staphylococcus aureus colonization in patients with atopic dermatitis in Sri Lanka. Clin Exp Dermatol 36:195–200
Jugeau S, Tenaud I, Knol AC et al. (2005) Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol 153:1105–13 Junghans V, Gutgesell C, Jung T et al. (1998) Epidermal cytokines IL-1beta, TNF-alpha, and IL-12 in patients with atopic dermatitis: response to application of house dust mite antigens. J Invest Dermatol 111:1184–8 Junghans V, Jung T, Neumann C (1996) Human keratinocytes constitutively express IL-4 receptor molecules and respond to IL-4 with an increase in B7/BB1 expression. Exp Dermatol 5:316–24 Kalali BN, Kollisch G, Mages J et al. (2008) Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-mediated differential signaling. J Immunol 181: 2694–704 Kerstan A, Brocker EB, Trautmann A (2011) Decisive role of tumor necrosis factor-alpha for spongiosis formation in acute eczematous dermatitis. Arch Dermatol Res 303:651–8 Kim HM, Park BS, Kim J et al. (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–17 Kim JY, Omori E, Matsumoto K et al. (2008) TAK1 is a central mediator of NOD2 signaling in epidermal cells. J Biol Chem 283:137–44 Kimber I, Cumberbatch M (1992) Stimulation of Langerhans cell migration by tumor necrosis factor alpha (TNF-alpha). J Invest Dermatol 99:48S–50S
Gober MD, Fishelevich R, Zhao Y et al. (2008) Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis. J Invest Dermatol 128:1460–9
Kinoshita H, Takai T, Anh Le T et al. (2009) Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. J Allergy Clin Immunol 123:179–86
Goh CL, Wong JS, Giam YC (1997) Skin colonization of Staphylococcus aureus in atopic dermatitis patients seen at the National Skin Centre, Singapore. Int J Dermatol 36:653–7
Kisich KO, Howell MD, Boguniewicz M (2007) The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on betadefensin 3. J Invest Dermatol 127:2368–80
Journal of Investigative Dermatology (2012), Volume 132
D Gutowska-Owsiak and GS Ogg Role of Keratinocytes
Kobayashi M, Yoshiki R, Sakabe J (2009) 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 160:297–304
activation by Staphylococcus aureus is toll-like receptor 2 but not tolllike receptor 4 or platelet activating factor receptor dependent. J Invest Dermatol 121:1389–96
Kock A, Schwarz T, Kirnbauer R (1990) Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 172:1609–14
Miller LS, Sorensen OE, Liu PT et al. (2005) TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J Immunol 174:6137–43
Kohka H, Yoshino T, Iwagaki H et al. (1998) Interleukin-18/interferongamma-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells. J Leukoc Biol 64:519–27
Mizutani H, Black R, Kupper TS (1991) Human keratinocytes produce but do not process pro-interleukin-1 (IL-1) beta. Different strategies of IL-1 production and processing in monocytes and keratinocytes. J Clin Invest 87:1066–71
Kollisch G, Kalali BN, Voelcker V et al. (2005) Various members of the Tolllike receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology 114:531–41 Kristensen M, Chu CQ, Eedy DJ et al. (1993) Localization of tumour necrosis factor-alpha (TNF-alpha) and its receptors in normal and psoriatic skin: epidermal cells express the 55-kD but not the 75-kD TNF receptor. Clin Exp Immunol 94:354–62 Kupper TS, Ballard DW, Chua AO et al. (1986) Human keratinocytes contain mRNA indistinguishable from monocyte interleukin 1 alpha and beta mRNA. Keratinocyte epidermal cell-derived thymocyte-activating factor is identical to interleukin 1. J Exp Med 164:2095–100 Lai Y, Gallo RL (2008) Toll-like receptors in skin infections and inflammatory diseases. Infect Disord Drug Targets 8:144–55 Laning JC, Isaacs CM, Hardin-Young J (1997) Normal human keratinocytes inhibit the proliferation of unprimed T cells by TGFbeta and PGE2, but not IL-10. Cell Immunol 175:16–24
Mkrtichyan M, Ghochikyan A, Movsesyan N et al. (2008) Immunostimulant adjuvant patch enhances humoral and cellular immune responses to DNA immunization. DNA Cell Biol 27:19–24 Molinero LL, Gruber M, Leoni J et al. (2003) Up-regulated expression of MICA and proinflammatory cytokines in skin biopsies from patients with seborrhoeic dermatitis. Clin Immunol 106:50–4 Moussion C, Ortega N, Girard J-P (2008) The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘Alarmin’? PLoS One 3:e3331 Muller-Anstett MA, Muller P, Albrecht T et al. (2010) Staphylococcal peptidoglycan co-localizes with Nod2 and TLR2 and activates innate immune response via both receptors in primary murine keratinocytes. PLoS One 5:e13153 Mutis T, De Bueger M, Bakker A et al. (1993) HLA class II+ human keratinocytes present Mycobacterium leprae antigens to CD4+ Th1-like cells. Scand J Immunol 37:43–51
Lebre MC, Antons JC, Kalinski P et al. (2003) 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 120:990–7
Naik SM, Cannon G, Burbach GJ et al. (1999) Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol 113:766–72
Lebre MC, van der Aar AM, van Baarsen L et al. (2007) Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 127:331–41
Nakae S, Naruse-Nakajima C, Sudo K et al. (2001) IL-1 alpha, but not IL-1 beta, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity. Int Immunol 13:1471–8
Lee HM, Shin DM, Choi DK et al. (2009) Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes. Cell Microbiol 11:678–92
Neill DR, Wong SH, Bellosi A et al. (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464:1367–70
Lee KH, Cho K-A, Kim J-Y et al. (2011) Filaggrin knockdown and Toll-like receptor 3 (TLR3) stimulation enhanced the production of thymic stromal lymphopoietin (TSLP) from epidermal layers. Exp Dermatol 20:149–51 Leonardi CL, Powers JL, Matheson RT et al. (2003) Etanercept as monotherapy in patients with psoriasis. N Engl J Med 349:2014–22 Little MC, Metcalfe RA, Haycock JW et al. (1998) The participation of proliferative keratinocytes in the preimmune response to sensitizing agents. Br J Dermatol 138:45–56 Liu L, Zhong Q, Tian T et al. (2010) Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nat Med 16:224–7 Luger TA, Stadler BM, Katz SI et al. (1981) Epidermal cell (keratinocyte)derived thymocyte-activating factor (ETAF). J Immunol 127:1493–8 Lundqvist EN, Back O (1990) Interleukin-1 decreases the number of Ia+ epidermal dendritic cells but increases their expression of Ia antigen. Acta Derm Venereol 70:391–4 Marble DJ, Gordon KB, Nickoloff BJ (2007) Targeting TNF[alpha] rapidly reduces density of dendritic cells and macrophages in psoriatic plaques with restoration of epidermal keratinocyte differentiation. J Dermatol Sci 48:87–101 Mascia F, Mariani V, Giannetti A et al. (2002) House dust mite allergen exerts no direct proinflammatory effects on human keratinocytes. J Allergy Clin Immunol 109:532–8 Matsuo K, Ishii Y, Quan YS et al. (2011) Transcutaneous vaccination using a hydrogel patch induces effective immune responses to tetanus and diphtheria toxoid in hairless rat. J Control Release 149:15–20 McKenzie RC, Arsenault TV, Sauder DN et al. (1990) Expression of interleukin1 beta in a human keratinocyte cell line. Lymphokine Res 9:391–403 Mempel M, Voelcker V, Kollisch G et al. (2003) Toll-like receptor expression in human keratinocytes: nuclear factor kappaB controlled gene
Nicola AV, Hou J, Major EO et al. (2005) Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway. J Virol 79:7609–16 Niebuhr M, Baumert K, Werfel T (2010) TLR-2-mediated cytokine and chemokine secretion in human keratinocytes. Exp Dermatol 19:873–7 Ogawa T, Takai T, Kato T et al. (2008) Upregulation of the release of granulocyte-macrophage colony-stimulating factor from keratinocytes stimulated with cysteine protease activity of recombinant major mite allergens, Der f 1 and Der p 1. Int Arch Allergy Immunol 146: 27–35 Ohto U, Fukase K, Miyake K et al. (2007) Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316:1632–4 Omori E, Matsumoto K, Sanjo H et al. (2006) TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem 281:19610–7 Otten HG, Bor B, Ververs C et al. (1996) Alloantigen-specific T-cell anergy induced by human keratinocytes is abrogated upon loss of cell-cell contact. Immunology 88:214–9 Pan G, French D, Mao W et al. (2001) Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice. J Immunol 167:6559–67 Papp KA, Tyring S, Lahfa M et al. (2005) A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 152:1304–12 Pastore S, Fanales-Belasio E, Albanesi C et al. (1997) Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin. J Clin Invest 99:3009–17 Pellegrini G, De Luca M, Orecchia G et al. (1992) Expression, topography, and function of integrin receptors are severely altered in keratinocytes from involved and uninvolved psoriatic skin. J Clin Invest 89:1783–95
www.jidonline.org
947
D Gutowska-Owsiak and GS Ogg Role of Keratinocytes
Pivarcsi A, Bodai L, Rethi B et al. (2003) Expression and function of Toll-like receptors 2 and 4 in human keratinocytes. Int Immunol 15:721–30 Pivarcsi A, Koreck A, Bodai L et al. (2004) Differentiation-regulated expression of Toll-like receptors 2 and 4 in HaCaT keratinocytes. Arch Dermatol Res 296:120–4 Plitz T, Saint-Mezard P, Satho M et al. (2003) IL-18 binding protein protects against contact hypersensitivity. J Immunol 171:1164–71 Pollock R, Chandran V, Barrett J et al. (2011) Differential major histocompatibility complex class I chain-related A allele associations with skin and joint manifestations of psoriatic disease. Tissue Antigens 77:554–61 Prens EP, Kant M, van Dijk G et al. (2008) IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis. J Invest Dermatol 128:932–8 Racz E, Prens EP, Kant M et al. (2011) Narrowband ultraviolet B inhibits innate cytosolic double-stranded RNA receptors in psoriatic skin and keratinocytes. Br J Dermatol 164:838–47 Romphruk AV, Romphruk A, Choonhakarn C et al. (2004) Major histocompatibility complex class I chain-related gene A in Thai psoriasis patients: MICA association as a part of human leukocyte antigen-B-Cw haplotypes. Tissue Antigens 63:547–54 Sauder DN, Carter CS, Katz SI et al. (1982) Epidermal cell production of thymocyte activating factor (ETAF). J Invest Dermatol 79:34–9 Schmitz J, Owyang A, Oldham E et al. (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–90 Schwarz A, Bhardwaj R, Aragane Y et al. (1995) Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells. J Invest Dermatol 104:922–7 Shi Z, Zeng M, Yang G et al. (2001) Protection against tetanus by needle-free inoculation of adenovirus-vectored nasal and epicutaneous vaccines. J Virol 75:11474–82 Smithgall MD, Comeau MR, Yoon BR et al. (2008) IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol 20: 1019–30 Soumelis V, Reche PA, Kanzler H et al. (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–80 Stoitzner P, Zanella M, Ortner U et al. (1999) Migration of langerhans cells and dermal dendritic cells in skin organ cultures: augmentation by TNFalpha and IL-1beta. J Leukoc Biol 66:462–70 Strange P, Skov L, Baadsgaard O (1994) Interferon gamma-treated keratinocytes activate T cells in the presence of superantigens: involvement of major histocompatibility complex class II molecules. J Invest Dermatol 102:150–4
948
Tigalonowa M, Bjerke JR, Livden JK et al. (1990) 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 70:385–90 Tohyama M, Sayama K, Komatsuzawa H et al. (2007) CXCL16 is a novel mediator of the innate immunity of epidermal keratinocytes. Int Immunol 19:1095–102 Trompette A, Divanovic S, Visintin A et al. (2009) Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457:585–8 Tyring S, Gordon KB, Poulin Y et al. (2007) Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 143:719–26 van de Kerkhof PC, Segaert S, Lahfa M et al. (2008) Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension. Br J Dermatol 159:1177–85 Van Kampen KR, Shi Z, Gao P et al. (2005) Safety and immunogenicity of adenovirus-vectored nasal and epicutaneous influenza vaccines in humans. Vaccine 23:1029–36 Voss E, Wehkamp J, Wehkamp K et al. (2006) NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281:2005–11 Walters CE, Ingham E, Eady EA et al. (1995) In vitro modulation of keratinocyte-derived interleukin-1 alpha (IL-1 alpha) and peripheral blood mononuclear cell-derived IL-1 beta release in response to cutaneous commensal microorganisms. Infect Immun 63:1223–8 Wang YH, Angkasekwinai P, Lu N et al. (2007) IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLPDC-activated Th2 memory cells. J Exp Med 204:1837–47 Wang Y-H, Ito T, Wang Y-H et al. (2006) Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietinactivated dendritic cells. Immunity 24:827–38 Watanabe S, Kano R, Sato H et al. (2001) The effects of Malassezia yeasts on cytokine production by human keratinocytes. J Invest Dermatol 116:769–73 Wittmann M, Purwar R, Hartmann C et al. (2005) Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases. J Invest Dermatol 124:1225–33 Wood LC, Elias PM, Calhoun C et al. (1996) Barrier disruption stimulates interleukin-1 alpha expression and release from a pre-formed pool in murine epidermis. J Invest Dermatol 106:397–403 Yu J, Cassels F, Scharton-Kersten T et al. (2002) Transcutaneous immunization using colonization factor and heat-labile enterotoxin induces correlates of protective immunity for enterotoxigenic Escherichia coli. Infect Immun 70:1056–68 Zahn S, Barchet W, Rehkamper C et al. (2011) Enhanced skin expression of melanoma differentiation-associated gene 5 (MDA5) in dermatomyositis and related autoimmune diseases. J Am Acad Dermatol 64:988–9
Szolnoky G, Bata-Csorgo Z, Kenderessy AS et al. (2001) A mannose-binding receptor is expressed on human keratinocytes and mediates killing of Candida albicans. J Invest Dermatol 117:205–13
Zhao Y, Fishelevich R, Petrali JP et al. (2008) Activation of keratinocyte protein kinase C zeta in psoriasis plaques. J Invest Dermatol 128:2190–7
Thomas DS, Ingham E, Bojar RA et al. (2008) In vitro modulation of human keratinocyte pro- and anti-inflammatory cytokine production by the capsule of Malassezia species. FEMS Immunol Med Microbiol 54:203–14
Zwirner NW, Dole K, Stastny P (1999) Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes. Human Immunol 60:323–30
Tian T, Liu L, Freyschmidt E-J et al. (2008) Overexpression of IL-1[alpha] in skin differentially modulates the immune response to scarification with vaccinia virus. J Invest Dermatol 129:70–8
Zwirner NW, Fernandez-Vina MA, Stastny P (1998) MICA, a new polymorphic HLA-related antigen, is expressed mainly by keratinocytes, endothelial cells, and monocytes. Immunogenetics 47:139–48
Journal of Investigative Dermatology (2012), Volume 132