Embed Size (px)
Citation preview
Inomata S, Matsunaga Y, Amano S et al. (2003)Possible involvement of gelatinases in base-ment membrane damage and wrinkle forma-tion in chronically ultraviolet B-exposedhairless mouse. J Invest Dermatol 120:128–34
Jantschitsch C, Majewski S, Maeda A et al. (2009)Infrared radiation confers resistance toUV-induced apoptosis via reduction of DNAdamage and upregulation of antiapoptoticproteins. J Invest Dermatol 129:1271–9
Krutmann J, Morita A, Chung JH (2012) Sunexposure: what molecular photodermatologytells us about its good and bad sides. J InvestDermatol 132:976–84
Martins I, Galluzzi L, Kroemer G (2011) Hormesis,cell death and aging. Aging (Albany NY) 3:821–8
Matsuda M, Hoshino T, Yamakawa N et al. (2013)Suppression of UV-induced wrinkle formationby induction of HSP70 expression in mice.J Invest Dermatol 133:919–28
Morita A, Torii K, Maeda A et al. (2009) Molecularbasis of tobacco smoke-induced premature
skin aging. J Investig Dermatol Symp Proc14:53–5
Piazena H, Kelleher DK (2010) Effects of infrared-Airradiation on skin: discrepancies in publisheddata highlight the need for an exact consid-eration of physical and photobiological lawsand appropriate experimental settings. Photo-chem Photobiol 86:687–705
Rattan SI, Fernandes RA, Demirovic D et al. (2009)Heat stress and hormetin-induced hormesis inhuman cells: effects on aging, wound heal-ing, angiogenesis, and differentiation. DoseResponse 7:90–103
Schieke S, Stege H, Kurten V et al. (2002) Infrared-A radiation-induced matrix metalloproteinase1 expression is mediated through extracellularsignal-regulated kinase 1/2 activation inhuman dermal fibroblasts. J Invest Dermatol119:1323–9
Vierkotter A, Schikowski T, Ranft U et al. (2010)Airborne particle exposure and extrinsic skinaging. J Invest Dermatol 130:2719–26
CD8 T Cells and IFN-g Emerge asCritical Players for Psoriasis in aNovel Model of Mouse PsoriasiformSkin InflammationPaola Di Meglio1 and Joao H. Duarte1
A pathogenic crosstalk between epithelial and immune cells underpins theaberrant immune and epidermal responses seen in psoriasis. Data from a novelmouse model of psoriasiform skin inflammation not only highlight the importanceof the interplay between keratinocytes, targets of genetic manipulation, andT cells as the major effector cells, but also reveal a critical role for CD8 T cells andIFN-g in disease initiation.
Journal of Investigative Dermatology (2013) 133, 871–874. doi:10.1038/jid.2012.426
The complex etiopathogenesis of psoriasisresults from the interaction of genetic andenvironmental factors, leading to dysregu-lated immune responses that manifest inthe skin as prominent epidermal hyper-plasia and an inflammatory infiltrate.Although a critical role for T cells is undis-puted, it has become increasingly evidentthat a pathogenic crosstalk between cellsof the innate and adaptive immune sys-tems, which also include keratinocytes
(KCs) as ancillary innate immune cells,underpins the aberrant immune and epi-dermal responses (Di Meglio et al., 2011).Psoriasis susceptibility genes identifiedthus far fall broadly into three cate-gories—tissue-specific, immunologicallyinnate, and immunologically adaptive(Capon et al., 2012)—further pointingtoward critical contributions from bothepithelial cells and immune cells indisease initiation.
See related article on pg 955
Contributions of mouse models ofpsoriasiform skin inflammation to diseaseunderstanding
Mouse models of psoriasiform skininflammation have been used sincethe early 1990s to elucidate themechanisms that underlie the humandisease (Gudjonsson et al., 2007). Forinstance, the description of a mousestrain with an intragenic deletion onthe sharpin gene affecting homeostaticNF-kB signaling was found to developskin inflammation spontaneously withsome similarities to psoriasis, such asepidermal thickening and intradermalmicroabscesses. Notably, however, itlacked other important pathologicalfeatures of human psoriatic lesions,such as epidermal T-cell infiltrates(HogenEsch et al., 1993). The extent towhich different mouse models canrecapitulate the entire scope ofpathological features of psoriasis is acommon discussion point—how faithfulcan a mouse model of psoriasis be,when mouse and human skin havesuch marked differences at structuraland cellular levels? In addition to thegenetic differences between the twospecies, the environmental challengesfor mice and humans are quite different,yet still very relevant for diseaseinitiation. By this time, the quest for asystem that could satisfactorily modelpsoriasis was just beginning, and inthe past decade a range of transge-nic (Gudjonsson et al., 2007) andpharmacological (van der Fits et al.,2009) models have been descri-bed, some of which recapitulate thehuman disease almost completely. Assuch, genetic manipulation of the signaltransducer and activator of transcription3 (STAT3), NF-kB, and AP-1 pathwaysin KC has yielded a number of differentmodels with different specificities, butall reproducing the epidermal structuralchanges and lymphocytic infiltratescommon to psoriasis and pointing tothe importance of the epithelial cellularcompartment in establishing psoriasi-form skin inflammation. On the otherhand, a different approach to modelingpsoriasis using a xenotransplantationmodel has emphasized the importanceof the lymphocytic compartment(Boyman et al., 2004; Conrad et al.,2007). By using human psoriatic skin
1Molecular Immunology, MRC National Institute for Medical Research, London, UK
Correspondence: Paola Di Meglio, Molecular Immunology, National Institute for Medical Research,The Ridgeway, London, NW7 1AA, UK. E-mail: [email protected]
COMMENTARY
www.jidonline.org 871
engrafted in immune-deficient mice, itbecame clear that CD4 and CD8 T cellsconstitute important effectors in thedisease through their production ofdisease-relevant cytokines.
Psoriasis immunopathogenesis
Analogous to other immune-mediateddisease, psoriasis has long been consid-ered a T helper (Th)-1-type and IFN-g-driven disease. Early studies foundincreased levels of IFN-g mRNA inlesional psoriatic skin and showed thatthe majority of epidermal T cells fromboth skin lesions and the peripheralblood of psoriatic patients producedIFN-g (Austin et al., 1999). These initialobservations were substantiated furtherby the identification of a strong IFN-ggenomic signature in lesional psoriaticskin (Bowcock et al., 2001). However,the discovery of IL-23 and theidentification of Th17 cells as majorplayers in autoimmunity set the scenefor a reevaluation of the immunopatho-genesis of psoriasis, with the focus shiftedto a pivotal role for the IL-23/IL-17 axis(Di Cesare et al., 2009). Analysis of thelymphocytic infiltrates in psoriatic skinshowed that both ab- (Lowes et al.,2008) and dermal gd-T cells (Cai et al.,2011) are responsible for the productionof IL-17 found in the skin, and a popula-tion of T cells coproducing IL-17A andIFN-g was identified in lesional skin(Lowes et al., 2008).
Although the recent focus of psoriasisresearch has been on Th cells, cytotoxicCD8 T (Tc)-cell involvement in diseasepathogenesis has also been suspected.Despite not forming a large proportionof lymphocytes in the skin, CD8 T cellshave been shown to be increased in theepidermis of lesional psoriatic skin(Hammar et al., 1984), where they are
ideally located to respond to potentialKC autoantigens on HLA class Imolecules, with the HLA-Cw0602*allele being the strongest geneticdeterminant for psoriasis (Capon et al.,2012). CD8 T cells participate not onlyin the production of IL-17A but also inthat of tumor necrosis factor (TNF) andIFN-g (Austin et al., 1999; Kryczek et al.,2008; Ortega et al., 2009). Of interest,the simultaneous expression of IFN-gand IL-17A has been associated withthe plastic properties of CD4 T cells(Hirota et al., 2011), where a switchin the transcriptional effector programhas been found to be responsible forpathological changes in other auto-immune diseases.
Ras overexpression in suprabasal KCsin mice results in a psoriasiform skinphenotype driven by CD8 T cells and IFN-cIn this issue of JID, Gunderson et al.(2013) show development of psoriasi-form skin inflammation, following doxy-cycline-dependent overexpression ofactivated H-Ras in suprabasal KCs.H-Ras is a member of the Rassuperfamily of small GTPases, whichwas identified as an oncogene 430years ago and is involved in a widerange of biological processes such ascell cycle progression, growth, migra-tion, cytoskeletal changes, apoptosis,and senescence (Fernandez-Medardeand Santos, 2011). The skin phenotypein Ras-overexpressing mice stronglyresembles human psoriasis, withbasal KC hyperproliferation, acanthosis,hyperkeratosis, intraepidermal neutro-phil microabscesses, and T-cell infilt-ration. Affected skin shows the typicalpsoriasis signature, with increasedmRNA levels of psoriasis-relevanttranscripts, including proinflammatory
cytokines (IL-23p19, TNF, G-CSF, andGM-CSF), chemokines (CXCL1, CCL2,and MIP-2), and antimicrobial peptides(DEFB-2, CAMP, S100A7A, S100A8,and S100A9). As such, most of thecellular and molecular players andstructural changes found in psoriaticskin were reproduced, pinpointing therelevance of this mouse as a suitablemodel of the disease.
This psoriasiform skin inflammationmodel required T cells for disease devel-opment because Ras overexpression ona Rag1� /� background abrogatedneutrophil recruitment and reduced skinacanthosis. Among infiltrating T cells,Th17 and Tc1/17 double producingIFN-g and IL-17A were increased sig-nificantly in the skin. However, onlyCD8 T- but not CD4 T-cell depletionreduced epidermal hyperproliferation,as well as skin and blood neutrophilia.Conversely, CD8 T-cell reconstitutionof Rag1� /� mice restored the skininflammation. Finally, the authors iden-tified IFN-g as a critical driving mediatorin this model, as IFN-g neutralization,but not IL-17A neutralization, bloc-ked CD8-mediated skin inflammationand KC hyperproliferation (Gundersonet al., 2013). These findings byGunderson et al. (2013) lend furthersupport to the importance of the inter-play between the epithelial and immunecompartment of the skin, put CD8T cells under the spotlight, and call fora reevaluation of the role of IFN-g indisease pathogenesis (Figure 1).
Although the genetic manipulationtriggering this murine model of psoriasi-form skin inflammation takes place inepidermal KCs, the full disease deve-loped only in the presence of CD8T cells. These findings support the viewthat the disease develops from an inter-action between ancillary KC and effec-tor immune cells. KCs initiate thispathogenic crosstalk by recruiting dis-ease-driving CD8 T cells, although howthis happens remains to be established, asthe nature of the interaction between KCsand CD8 T cells remains unknown. It hasbeen reported that Ras activation is higherin psoriatic lesions (Lin et al., 1999),providing further support to the validityof the model. However, how would Rasactivation result in increased recruitmentand activation of CD8 T cells? It could be
Clinical Implications� The pathogenic crosstalk between the epithelial and immune compart-
ments in the skin underpins the aberrant immune and epidermalresponses seen in Ras-overexpressing mice and psoriasis.
� CD8 T cells are capable of orchestrating psoriasiform skin inflammation,and their contributions to the pathogenesis of psoriasis should be thefocus of further investigation.
� IFN-g is a critical mediator in psoriasiform skin inflammation, calling for areevaluation of its usefulness as a therapeutic target in treating psoriasis.
COMMENTARY
872 Journal of Investigative Dermatology (2013), Volume 133
hypothesized that the increased prolifera-tion status of the Ras-transformed KCsresults in an alteration in their differentia-tion program, with an impact on theiractivation state. One possibility is that Ras-overexpressing KCs produce increasedamounts of chemotactic CXCL16, whichhas been recently shown to mediatehoming of CD8 T cells into human skinthrough interaction with CXCR6, preferen-tially expressed on CD8 T cells (Guntheret al., 2012).
In particular, the mouse model ofpsoriasiform inflammation developedby Gunderson et al. (2013) sheds newlight on the contributions of CD8 T cellsin psoriasis.
Although they represent only 5% of theskin-infiltrating lymphocytes in Ras-over-expressing mice, CD8 T cells were capableof initiating psoriasiform skin inflamma-tion. They produce both IFN-g and IL-17A,favor neutrophil recruitment and micro-abscess formation, enhance KC prolifera-tion, and aid in CD4 T-cell activation. Inparticular, CD8 T cells favor CD4 T-cellinfiltration into the skin and also affectthe frequency of IL-17-producing gd andTh17 cells, suggesting that a previouslyunappreciated proinflammatory axis existsbetween CD8 and CD4/gd-T cells.
As occurs in psoriatic lesions, CD8T cells accumulated preferentially in theepidermis of the Ras-overexpressingmice, where they were strategicallylocated to interact with KCs. Conradet al. (2007) showed that expansion ofepidermal rather than dermal T cellscorrelated with disease progression inthe AGR129 mice xenotransplantationmodel of psoriasis. Moreover, neutra-lization of very-late antigen-1/a1b1integrin, expressed on epidermal Tcells, blocked epidermal infiltrationand prevented psoriasis development(Conrad et al., 2007). It is possible thatCD8 T-cell localization is a key deter-minant of the tissue-specific immuneresponse and is critical for their patho-genicity in psoriasis. However, the pre-sence of cytotoxic CD8 T-cell-expres-sing perforin and granzyme B stillremains to be reconciled with adisease characterized by cell hyper-proliferation and reduced apoptosis.
One of the most unexpected findingsshown in the Ras-overexpressing mousemodel is the striking importance ofIFN-g over that of IL-17A in drivingdisease pathogenesis. While IFN-g drivesdisease development, IL-17A seems tohave a minor role and perhaps intervenes
only in the subsequent amplification ofthe skin inflammation. Whether this is anintrinsic feature of the model remains tobe tested; however, accumulating evi-dence in the literature encourages a reas-sessment of the contribution of IFN-g topsoriasis pathogenesis. Although IFN-g isknown to inhibit the production of IL-17by T cells in vitro, recent studies suggestthat it can program dendritic cells toproduce IL-23 and IL-1, promoting IL-17production by memory T cells (Kryczeket al., 2008). Therefore, it is possible thatCD8 T-cell-derived IFN-g promoted theincreased frequency of IL-17-producing Tcells in the skin of Ras-overexpressingmice through this mechanism. Moreover,Johnson-Huang et al. (2012) have recentlyshown that a single intradermal injectionof IFN-g in nonlesional skin of psoriasispatients is capable of inducing severalmolecular and histological features char-acteristic of psoriatic lesions (increasedexpression of chemokines, S100 familymembers, and adhesion molecule genes,as well as influx of T cells and inflam-matory dendritic cells), despite not cau-sing visible changes in the skin (Johnson-Huang et al., 2012).
Neutralization of IFN-g in RAS-over-expressing mice markedly affected KCproliferation (Gunderson et al., 2013).Although IFN-g is known to inhibit pri-mary KC growth in vitro, altered responsesto IFN-g have been shown in psoriatic KCs(Baker et al., 1988). In this regard, it is alsoworth mentioning that regular cutaneousinjections of IFN-g, administrated topatients in an early attempt to use it as atherapeutic for several immune-mediateddiseases (including psoriasis; Fierlbecket al., 1990), caused a ‘‘psoriasis-like’’injection-site reaction, characterized byinduration, erythema, epithelial thicken-ing, and accumulation of T cells andmonocytes in the dermis.
Although additional studies on therole of IFN-g are required using othermodel systems, it is nevertheless tempt-ing to translate these findings into aclinical scenario. Fentolizumab, ananti-IFN-g mAb, has shown some effi-cacy in Crohn’s disease (Reinisch et al.,2010). However, no data are availableregarding IFN-g blocking in psoriaticpatients, although this approach hadbeen suggested over 9 years ago(Skurkovich and Skurkovich, 2003).
Ras Ras Ras
CXCL-16
Blood vessel
IFN-γ
IL-17A
IL-17A
Th17Th17
Th17
γδ T
γδ T
IL-1IL-23
DC
TNF
IFN-γ IL-17ATNF
IFN-γ
CXCL1
S100A7S100A8S100A9DEFB-2CAMP
NN
N N
N N
CCL2MIP-2
CXCR6 VLA-1
Tc1/17Tc1/17
Tc1/17
Tc1/17Tc1/17
Figure 1. CD8 T cells mediate Ras-induced psoriasis-like skin inflammation through IFN-c.
Overexpression of activated Ras in suprabasal keratinocytes (KC) resulted in psoriasiform skin inflammation
with skin acanthosis, hyperkeratosis, and intraepidermal neutrophil (N) and T-cell infiltration, including
IL-17Aþ IFN-gþ CD8þ T cytotoxic (Tc1/17) cells. Ras-overexpressing KCs might recruit Tc1/17 cells
through the release of CXCL16 interacting with CXCR6 specifically expressed on CD8þ T cells, also
possibly bearing very-late antigen (VLA-1) expression, which favors epidermal localization. Proinflammatory
cytokines released by Tc1/17 cells, especially IFN-g, enhance KC activation and proliferation, promoting KC
production of neutrophil-attractant CXCL1 and S100 family members (S100A7, S100A8, and S100A9).
Moreover, IFN-g favors Th-17 and IL-17þ gd-T-cell infiltration into the skin, possibly by programming
dendritic cells to produce IL-17-driving cytokines IL-23 and IL-1 and chemoattracting CCL2 and MIP-2.
COMMENTARY
www.jidonline.org 873
The success of anti-TNF agents, as wellas the more recent outburst of highlyeffective biologics targeting the IL-23/IL-17 axis, should not overshadow the factthat there is still a sizable number ofnonresponder patients who mightbenefit by an alternative strategy.
The mouse model described byGunderson et al. (2013) uncoversan important aspect of CD8 T-cellpathogenicity in skin inflammationmediated by IFN-g, while posing newcritical questions. Answering them willenhance our understanding of thepathological mechanisms underlyingpsoriasis and could ultimately lead tonovel effective therapeutic strategies.
CONFLICT OF INTERESTThe authors state no conflict of interest.
ACKNOWLEDGMENTSWe thank B Stockinger for critical reading of themanuscript. PDM and JHD are supported by anEuropean Research Council Advanced Grantawarded to Dr Stockinger.
REFERENCES
Austin LM, Ozawa M, Kikuchi T et al. (1999) Themajority of epidermal T cells in Psoriasisvulgaris lesions can produce type 1 cytokines,interferon-gamma, interleukin-2, and tumornecrosis factor-alpha, defining TC1 (cytotoxicT lymphocyte) and TH1 effector populations:a type 1 differentiation bias is also measuredin circulating blood T cells in psoriaticpatients. J Invest Dermatol 113:752–9
Baker BS, Powles AV, Valdimarsson H et al. (1988)An altered response by psoriatic keratinocytes togamma interferon. Scand J Immunol 28:735–40
Bowcock AM, Shannon W, Du F et al. (2001)Insights into psoriasis and other inflammatorydiseases from large-scale gene expressionstudies. Hum Mol Genet 10:1793–805
Boyman O, Hefti HP, Conrad C et al. (2004)Spontaneous development of psoriasis in anew animal model shows an essential role forresident T cells and tumor necrosis factor-alpha. J Exp Med 199:731–6
Cai Y, Shen X, Ding C et al. (2011) Pivotal role ofdermal IL-17-producing gammadelta T cellsin skin inflammation. Immunity 35:596–610
Capon F, Burden AD, Trembath RC et al. (2012)Psoriasis and other complex trait dermatoses:from Loci to functional pathways. J InvestDermatol 132:915–22
Conrad C, Boyman O, Tonel G et al. (2007)Alpha1beta1 integrin is crucial for accumula-tion of epidermal T cells and the developmentof psoriasis. Nat Med 13:836–42
Di Cesare A, Di Meglio P, Nestle FO (2009) TheIL-23/Th17 axis in the immunopathogenesisof psoriasis. J Invest Dermatol 129:1339–50
Di Meglio P, Perera GK, Nestle FO (2011)The multitasking organ: recent insights intoskin immune function. Immunity 35:857–869
Fernandez-Medarde A, Santos E (2011) Ras incancer and developmental diseases. GenesCancer 2:344–58
Fierlbeck G, Rassner G, Muller C (1990) Psoriasisinduced at the injection site of recombinantinterferon gamma. Results of immunohistolo-gic investigations. Arch Dermatol 126:351–5
Gudjonsson JE, Johnston A, Dyson M et al. (2007)Mouse models of psoriasis. J Invest Dermatol127:1292–308
Gunderson A, Mohammed J, Horvath F et al.(2013) CD8þ T cells mediate RAS-inducedPsoriasis-like skin inflammation throughIFN-g. J Invest Dermatol 133:955–63
Gunther C, Carballido-Perrig N, Kaesler S et al.(2012) CXCL16 and CXCR6 are upregulatedin psoriasis and mediate cutaneous recruit-ment of human CD8þ T cells. J InvestDermatol 132:626–34
Hammar H, Gu SQ, Johannesson A et al. (1984)Subpopulations of mononuclear cells inmicroscopic lesions of psoriatic patients.Selective accumulation of suppressor/cyto-toxic T cells in epidermis during the evolutionof the lesion. J Invest Dermatol 83:416–20
Hirota K, Duarte JH, Veldhoen M et al. (2011) Fatemapping of IL-17-producing T cells in inflam-matory responses. Nat Immunol 12:255–63
HogenEsch H, Gijbels MJ, Offerman E et al. (1993)A spontaneous mutation characterized bychronic proliferative dermatitis in C57BLmice. Am J Pathol 143:972–82
Johnson-Huang LM, Suarez-Farinas M, Pierson KCet al. (2012) A single intradermal injection ofIFN-gamma induces an inflammatory state inboth non-lesional psoriatic and healthy skin.J Invest Dermatol 132:1177–87
Kryczek I, Bruce AT, Gudjonsson JE et al. (2008) Induc-tion of IL-17þ T cell trafficking and developmentby IFN-gamma: mechanism and pathologicalrelevance in psoriasis. J Immunol 181:4733–41
Lin P, Baldassare JJ, Voorhees JJ et al. (1999)Increased activation of Ras in psoriatic lesions.Skin Pharmacol Appl Skin Physiol 12:90–7
Lowes MA, Kikuchi T, Fuentes-Duculan J et al.(2008) Psoriasis vulgaris lesions contain dis-crete populations of Th1 and Th17 T cells.J Invest Dermatol 128:1207–11
Ortega C, Fernandez AS, Carrillo JM et al. (2009) IL-17-producing CD8þ T lymphocytes from psoriasisskin plaques are cytotoxic effector cells that secreteTh17-related cytokines. J Leukoc Biol 86:435–43
Reinisch W, de Villiers W, Bene L et al. (2010)Fontolizumab in moderate to severe Crohn’sdisease: a phase 2, randomized, double-blind,placebo-controlled, multiple-dose study.Inflamm Bowel Dis 16:233–42
Skurkovich B, Skurkovich S (2003) Anti-interferon-gamma antibodies in the treatment of auto-immune diseases. Curr Opin Mol Ther 5:52–7
van der Fits L, Mourits S, Voerman JS et al. (2009)Imiquimod-induced psoriasis-like skin inflam-mation in mice is mediated via the IL-23/IL-17axis. J Immunol 182:5836–45
Toll-Like Receptors Link Atopic Marchto the Hygiene HypothesisLajos Kemeny1,2 and Kornelia Szabo1
In recent decades, the prevalence of atopic diseases has increased substantiallyworldwide, but their molecular pathologies are now being elucidated. The reportby Haapakoski et al. in this issue suggests that the manner in which the immunesystem encounters an allergen is key to the subsequent polarization of itsresponses, and the presence of microbial ligands appears to be important in thisprocess. Data in this report provide further proof of the hygiene hypothesis thatcombine it with known features of the atopic march.
Journal of Investigative Dermatology (2013) 133, 874–878. doi:10.1038/jid.2013.11
The hygiene hypothesis was first intro-duced in 1989 by David P Strachan,who proposed, based on epidemiological
studies, that changes in personal hygiene,improvements in household amenities,and declining family sizes had been
See related article on pg 964
1MTA-SZTE Dermatological Research Group, Szeged, Hungary and 2Department of Dermatology andAllergology, University of Szeged, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, Szeged,Hungary
Correspondence: Lajos Kemeny, Department of Dermatology and Allergology Dermatological ResearchGroup of the Hungarian Academy of Sciences, Koranyi fasor 6, Szeged, H-6720, Hungary.E-mail: [email protected]
COMMENTARY
874 Journal of Investigative Dermatology (2013), Volume 133
