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Psoriasis Plays a Wild CARD

  • Elien Van Nuffel
    Affiliations
    Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium

    Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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  • Inna S. Afonina
    Affiliations
    Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium

    Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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  • Rudi Beyaert
    Correspondence
    Correspondence: Rudi Beyaert, Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, Ghent University-VIB, Technologiepark 927, Ghent 9052, Belgium.
    Affiliations
    Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium

    Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    Search for articles by this author
      Rare autosomal mutations in CARD14 have previously been linked to psoriasis susceptibility in humans, but their pathogenic role had not been shown. Mellett et al. generated mice harboring the patient-derived gain-of-function Card14ΔE138 mutation and showed that hyperactivation of CARD14 alone is sufficient to induce immunopathogenic mechanisms that are responsible for psoriasis, which is driven by the IL-17/IL-23 axis.
      Mice expressing a gain-of-function mutant of CARD14 are a novel mouse model for human psoriasis.
      Psoriasis is a common chronic inflammatory skin disease that has a serious impact on the quality of life of affected patients. Plaque psoriasis, which is the most common type of psoriasis and is also known as psoriasis vulgaris, is characterized by the emergence of red, scaly, and sharply demarcated plaques that result from the pathogenic interplay between hyperproliferative keratinocytes and activated immune cells. Less common types of psoriasis include pustular, inverse, erythrodermic, and guttate psoriasis. Genome-wide association studies have shown that genetic factors play an important role in the etiology of psoriasis. Rare highly penetrant mutations in CARD14 have been associated with plaque psoriasis, and CARD14 accounts for the elusive PSORS2 locus association (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ). CARD14 mutations have also been linked to clinically related conditions such as psoriatic arthritis, generalized pustular psoriasis, and pityriasis rubra pilaris (reviewed by
      • Van Nuffel E.
      • Schmitt A.
      • Afonina I.S.
      • Schulze-Osthoff K.
      • Beyaert R.
      • Hailfinger S.
      CARD14-mediated activation of paracaspase MALT1 in keratinocytes: implications for psoriasis.
      ). CARD14 is an intracellular scaffold protein that is prominently expressed in keratinocytes and mediates NF-κB activation through the formation of a CBM (CARD14-BCL10-MALT1) signaling complex. Gain-of-function mutations in CARD14 enhance CBM complex formation and downstream NF-κB signaling, leading to production of psoriasis-associated cytokines and chemokines by cultured keratinocytes (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Howes A.
      • O’Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ). However, follow-up studies have been limited, so the functional and physiological effects of CARD14 mutations in vivo were unknown.
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      show that heterozygous expression of a gain-of-function CARD14 mutation that was originally identified in patients led to spontaneous psoriasiform inflammation in mice (
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      ).

      A CARD14 mutation is sufficient to induce psoriasiform inflammation in mice

      To investigate the pathological role of a CARD14 mutation,
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      used CRISPR/Cas-mediated genome editing to generate mice expressing CARD14 with a deletion of residue E138 (Figure 1). This variant was originally described in a patient suffering from pityriasis rubra pilaris type V. Additional mutations affecting the same residue—CARD14E138A and CARD14E138K—have been linked to generalized pustular psoriasis and pityriasis rubra pilaris. Mice that expressed one Card14ΔE138 allele developed spontaneous psoriasiform disease that was characterized by scaling skin lesions and mainly affected the ears and tail. Histological analysis of affected skin showed typical hallmarks of human psoriasis such as epidermal acanthosis, hyperkeratosis, parakeratosis, hyperproliferating keratinocytes, and immune cell infiltration. Analysis of the infiltrating immune cells in involved ears showed marked increases in neutrophils, myeloid antigen-presenting cells, and αβ and γδ T cells (
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      ).
      Figure 1
      Figure 1CARD14 mutation in mice induces immunological responses, which culminate in psoriasiform inflammation. Heterozygous expression of the gain-of-function mutation Card14ΔE138 in mice strongly enhances CARD14-BCL10-MALT1 complex formation in keratinocytes and, in this way, drives hyperactivation of NF-κB. This leads to transcription of several chemokines (CCL20, CXCL1, and CXCL2), cytokines (IL-36 and IL-19), and antimicrobial peptides, followed by recruitment and activation of neutrophils, dendritic cells, and T cells. Activated dendritic cells release IL-23, which drives expression of IL-17 and IL-22 in T cells. AMP, antimicrobial peptides.
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      also showed that transcriptomic profiles of affected ear tissue of Card14ΔE138-expressing mice strongly resembled those of human plaque psoriasis skin. Several cytokines that are central in the IL-17/IL-23 axis of psoriasis pathogenesis (e.g., Il17f, Il19, Il22, and Il23p19) were strongly up-regulated. Chemokines (e.g., Ccl20, Cxcl1, and Cxcl2), antimicrobial peptides (e.g., Defb4, S100a7, and Lcn2), and proinflammatory cytokines (e.g., Il36γ and Il17c) that are typically produced by activated keratinocytes to sustain and amplify skin inflammation during psoriasis were also induced. Selected molecules that are involved in the formation of the cornified envelope and the skin barrier were also increased (e.g., Ivl, Lce3b, Lce3c, and Flg1), which is consistent with the intact skin barrier observed in Card14ΔE138 mice. Mechanistically, Mellet et al. expanded on previous studies that reported that psoriasis-associated CARD14 mutants drove enhanced CBM complex formation and activation of MALT1 proteolytic activity (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Howes A.
      • O’Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ). Mellett et al. point out that the CBM complex was hyperactivated in keratinocytes that were isolated from Card14ΔE138-expressing mice (
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      ). Taken together, these data show that heterozygous expression of the gain-of-function mutant Card14ΔE138 is sufficient to drive the immunological and clinical phenotype of plaque-type psoriasis in mice (
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      ), further strengthening the hypothesis that CARD14 signaling is part of a pivotal pathway in psoriasis pathogenesis. Consistent with this, mice deficient in CARD14 were recently shown to be partially protected from imiquimod- and IL-23–induced “psoriasis” (
      • Tanaka M.
      • Kobiyama K.
      • Honda T.
      • Uchio-Yamada K.
      • Natsume-Kitatani Y.
      • Mizuguchi K.
      • et al.
      Essential role of CARD14 in murine experimental psoriasis.
      ), suggesting that CARD14 signaling can be activated in the absence of CARD14 mutations.

      Card14ΔE138 mice as a novel mouse model for psoriasis

      The modeling of human psoriasis in vivo through the use of mouse models represents a powerful laboratory tool for investigating the immunological and genetic mechanisms contributing to psoriasis in patients. Although no single psoriasis-like mouse model is likely to replicate the totality of human psoriasis and mice have several obvious cellular and anatomic differences from humans, in vivo systems are indispensable tools for advancing our understanding of the immunological and molecular basis of this inflammatory condition. In this context, the transgenic Card14ΔE138 mice described by
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      display numerous histopathological features of human psoriasis and exhibit similar gene expression profiles. To determine if psoriasiform inflammation in Card14ΔE138-expressing mice responded to an established psoriasis therapy, Mellett et al. treated these mice with an IL-23p19 neutralizing antibody, reducing the psoriatic phenotype and the expression of antimicrobial peptides and proinflammatory cytokines (
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      ). This provides additional support for the clinical relevance of the Card14ΔE138 transgenic mouse model.
      Moreover, the protective effect of IL-23–neutralizing antibodies suggests that targeting IL-23 might be a valid therapeutic approach for psoriasis patients with CARD14 mutations. Ustekinumab, an IL-12/IL-23 inhibitor, showed beneficial effects in pityriasis rubra pilaris patients with CARD14 mutations (
      • Lwin S.M.
      • Hsu C.K.
      • Liu L.
      • Huang H.Y.
      • Levell N.J.
      • McGrath J.A.
      Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
      ). Thus, Card14ΔE138 transgenic mice are a relevant mouse model for evaluating therapeutic options for patients with genetic defects in CARD14. In this context, because CARD14ΔE138 activates MALT1 proteolytic activity, small compound MALT1 inhibitors might also have beneficial effects. It is also worth mentioning that the role of CARD14 in the pathogenesis of psoriasis may not be limited to cases where CARD14 gain-of-function mutations are present, as already suggested by the protection of CARD14-deficient mice in imiquimod- and IL-23–inducible murine models of psoriasis (
      • Tanaka M.
      • Kobiyama K.
      • Honda T.
      • Uchio-Yamada K.
      • Natsume-Kitatani Y.
      • Mizuguchi K.
      • et al.
      Essential role of CARD14 in murine experimental psoriasis.
      ). CARD14 expression has also been shown to be up-regulated in lesional psoriatic skin (
      • Jabbari A.
      • Suarez-Farinas M.
      • Dewell S.
      • Krueger J.G.
      Transcriptional profiling of psoriasis using RNA-seq reveals previously unidentified differentially expressed genes.
      ), and a CARD14 single nucleotide polymorphism was linked to psoriasis susceptibility in a gnome-wide association study (
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • Ellinghaus E.
      • Stuart P.E.
      • Capon F.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ). Therefore, Card14ΔE138 mice will be an interesting mouse model to study the underlying molecular and immunological mechanisms of psoriasis due to uncontrolled CARD14 signaling in general.

      Future directions

      Even though the report of
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      clearly shows a physiological role for Card14 mutations in the pathogenesis of psoriasis, several open questions remain to be answered. First, the psoriasiform lesions of Card14ΔE138 mice are mainly restricted to the ears, tail, and around the eyes. Such site-specific differences in skin responses might reflect anatomical, immunological, and microbiological differences in skin from different areas of the body. However, it remains enigmatic why some skin sites are more prone to skin inflammation induced by Card14ΔE138 expression than others.
      Second, it is not yet clear if the psoriasiform skin inflammation in Card14ΔE138 mice is solely the result of keratinocyte-intrinsic effects or if it might be influenced by the expression of Card14ΔE138 in other cell types such as immune and endothelial cells. In the study of
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      , keratinocytes of Card14ΔE138 mice showed enhanced CBM complex formation and increased transcription of proinflammatory cytokines (Il17c, Il19, and Il36γ). However, it is not known if keratinocyte-intrinsic changes alone can kindle psoriasiform skin inflammation. Furthermore, it has previously been suggested that CARD14 in γδ T cells might play a role in imiquimod-induced psoriasis (
      • Tanaka M.
      • Kobiyama K.
      • Honda T.
      • Uchio-Yamada K.
      • Natsume-Kitatani Y.
      • Mizuguchi K.
      • et al.
      Essential role of CARD14 in murine experimental psoriasis.
      ). It will be important to assess the development of skin inflammation in mice expressing Card14ΔE138 in specific cell types. In this context, the finding of Mellett et al. that homozygous Card14ΔE138 mice die soon after birth might point to a role for enhanced CARD14 signaling in other cell types.
      Third, although the study of
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      shows that a Card14 mutation is sufficient to drive psoriasiform inflammation, the fact that in humans different CARD14 mutations are associated with different disease severity or different types of cutaneous inflammation (
      • Van Nuffel E.
      • Schmitt A.
      • Afonina I.S.
      • Schulze-Osthoff K.
      • Beyaert R.
      • Hailfinger S.
      CARD14-mediated activation of paracaspase MALT1 in keratinocytes: implications for psoriasis.
      ) suggests that additional factors may contribute to disease pathogenesis. Relevant factors may include environmental triggers or possibly epigenetic alterations.
      Finally, the role of wild-type CARD14 in normal skin, as well as the endogenous or environmental factors that regulate its activity in normal and diseased skin, are still largely unexplored. Defining the role of CARD14 in normal skin homeostasis and finding upstream ligands and receptors may lead to development of alternative therapeutic strategies.
      In conclusion, the study of
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.
      • et al.
      CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
      not only provides new insights into the physiological consequences of uncontrolled CARD14 signaling, it also provides the scientific community with a valuable new mouse model for further mechanistic studies and the testing of novel therapeutic approaches for human psoriasis.

      ORCID

      References

        • Afonina I.S.
        • Van Nuffel E.
        • Baudelet G.
        • Driege Y.
        • Kreike M.
        • Staal J.
        • et al.
        The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
        EMBO Rep. 2016; 17: 914-927
        • Howes A.
        • O’Sullivan P.A.
        • Breyer F.
        • Ghose A.
        • Cao L.
        • Krappmann D.
        • et al.
        Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
        Biochem J. 2016; 473: 1759-1768
        • Jabbari A.
        • Suarez-Farinas M.
        • Dewell S.
        • Krueger J.G.
        Transcriptional profiling of psoriasis using RNA-seq reveals previously unidentified differentially expressed genes.
        J Invest Dermatol. 2012; 132: 246-249
        • Jordan C.T.
        • Cao L.
        • Roberson E.D.
        • Duan S.
        • Helms C.A.
        • Nair R.P.
        • et al.
        Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
        Am J Hum Genet. 2012; 90: 796-808
        • Jordan C.T.
        • Cao L.
        • Roberson E.D.
        • Pierson K.C.
        • Yang C.F.
        • Joyce C.E.
        • et al.
        PSORS2 is due to mutations in CARD14.
        Am J Hum Genet. 2012; 90: 784-795
        • Lwin S.M.
        • Hsu C.K.
        • Liu L.
        • Huang H.Y.
        • Levell N.J.
        • McGrath J.A.
        Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
        Br J Dermatol. 2018; 178: 969-972
        • Mellett M.
        • Meier B.
        • Mohanan D.
        • Schairer R.
        • Cheng P.
        • Satoh T.
        • et al.
        CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17—mediated psoriasiform skin inflammation in vivo.
        J Invest Dermatol. 2018; 138: 2010-2023
        • Tanaka M.
        • Kobiyama K.
        • Honda T.
        • Uchio-Yamada K.
        • Natsume-Kitatani Y.
        • Mizuguchi K.
        • et al.
        Essential role of CARD14 in murine experimental psoriasis.
        J Immunol. 2018; 200: 71-81
        • Tsoi L.C.
        • Spain S.L.
        • Knight J.
        • Ellinghaus E.
        • Stuart P.E.
        • Capon F.
        • et al.
        Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
        Nat Genet. 2012; 44: 1341-1348
        • Van Nuffel E.
        • Schmitt A.
        • Afonina I.S.
        • Schulze-Osthoff K.
        • Beyaert R.
        • Hailfinger S.
        CARD14-mediated activation of paracaspase MALT1 in keratinocytes: implications for psoriasis.
        J Invest Dermatol. 2017; 137: 569-575

      Linked Article

      • CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17–Mediated Psoriasiform Skin Inflammation In Vivo
        Journal of Investigative DermatologyVol. 138Issue 9
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          Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration.
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