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Pushing the Envelope in Psoriasis: Late Cornified Envelope Proteins Possess Antimicrobial Activity

  • Nathan K. Archer
    Affiliations
    Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Migena N. Dilolli
    Affiliations
    Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Lloyd S. Miller
    Correspondence
    Correspondence: Lloyd S. Miller, Johns Hopkins Department of Dermatology, Cancer Research Building II, Suite 205, 1550 Orleans Street, Baltimore, Maryland 21231, USA.
    Affiliations
    Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland, USA
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      Deletion of late cornified envelope (LCE) genes LCE3B and LCE3C (LCE3B/C-del) is a psoriasis risk factor linked to the major psoriasis risk gene HLA-C*06. Niehues et al. demonstrate that LCE3B/C-del leads to increased keratinocyte LCE3A expression. They also show that LCE3A/B/C possess antimicrobial activity but do not obviously regulate epidermal barrier integrity. These findings implicate LCE proteins in psoriasis pathogenesis via a new functional role.
      • The LCE3B/C-del mutation results in increased epidermal LCE3A expression.
      • LCE3A, LCE3B, and LCE3C proteins possess broad-spectrum antimicrobial activity.
      • LCE3B/C-del might alter antigen exposure to elicit HLA-C*06:02 restricted immune responses.

      Gene polymorphisms in psoriasis

      Psoriasis is a common inflammatory skin disease that is thought to primarily be mediated by dysregulated T helper type 1 (Th1) and Th17 immune responses (
      • Nestle F.O.
      • Kaplan D.H.
      • Barker J.
      Psoriasis.
      ). Psoriasis also has a genetic predisposition, and recent genome-wide association studies have identified more than 60 susceptibility loci that account for 20–25% of the heritability of psoriasis (
      • 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.
      ). The functional consequences of these gene associations in psoriasis have been difficult to study, although therapeutic targeting of blockade of tumor necrosis factor, IL-12, and IL-23 supports important roles of genetic variations in TNFAIP3, IL12B, and IL23R (
      • Johnston A.
      • Xing X.
      • Swindell W.R.
      • Kochkodan J.
      • Riblett M.
      • Nair R.P.
      • et al.
      Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis.
      ,
      • Tejasvi T.
      • Stuart P.E.
      • Chandran V.
      • Voorhees J.J.
      • Gladman D.D.
      • Rahman P.
      • et al.
      TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis.
      ). This is especially the case with two of the strongest genetic risk factors associated with psoriasis including the major histocompatibility complex class I gene HLA-C*06:02 (odds ratio ∼2.6–5) (also known as PSORS1) and deletion of late cornified envelope (LCE) genes LCE3B and LCE3C (LCE3B/C-del) (odds ratio of ∼1.3) (also known as PSORS4) (
      • Huffmeier U.
      • Bergboer J.G.
      • Becker T.
      • Armour J.A.
      • Traupe H.
      • Estivill X.
      • et al.
      Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors.
      ,
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ).

      Consequences of the LCE3B/C-del in psoriasis

      • Niehues H.
      • Tsoi L.C.
      • van der Krieken D.A.
      • Jansen P.A.M.
      • Oortveld M.A.W.
      • Rodijk-Olthuis D.
      • et al.
      Psoriasis-associated late cornified envelope (LCE) proteins have antibacterial activity.
      investigated the effect of LCE3B/C-del in normal skin and in psoriasis lesional skin and found that this deletion resulted in markedly increased expression of LCE3A in the normal skin of patients and a 100-fold higher expression in psoriasis skin (Figure 1a and b ). Interestingly, in humans without this mutation (wt/wt), LCE3A expression was completely absent in normal skin but similarly increased in psoriasis skin. This was likely due to the action of Th1 and Th17 cytokines, which led to upregulation of LCE3 proteins in 3D human skin reconstructed cultures. In particular, the addition of Th1 cytokines to reconstructed human skin cultures possessing LCE3B/C-del mutations led to selective and marked upregulation of LCE3A.
      Figure 1
      Figure 1Antimicrobial activity of LCE proteins in normal skin and psoriasis. (a) Compared with normal skin (wt/wt), the skin from individuals with the LCE3B/C-del has constitutive expression of LCE3A, which has antimicrobial activity against bacteria in the skin microbiome. (b) In lesional psoriasis skin, wt/wt individuals have markedly increased expression of LCE3A, LCE3B, and LCE3C, whereas individuals with the LCE3B/C-del only have upregulated LCE3A. All have broad-spectrum antimicrobial activity against bacteria in the skin microbiome. Altered self or microbial antigen exposure in the setting of LCE3B/C-del might elicit HLA-C*06:02 restricted immune responses, providing an explanation for the epistatic relationship between these two psoriasis gene susceptibility loci. LCE, late cornified envelope.

      LCE proteins are not involved in maintaining the skin barrier

      LCE genes produce a family of proteins with unknown functions, but their expression is limited to the epidermis. Given this anatomical location, LCE proteins were previously assumed to be involved in epidermal barrier integrity. To assess this potential role,
      • Niehues H.
      • Tsoi L.C.
      • van der Krieken D.A.
      • Jansen P.A.M.
      • Oortveld M.A.W.
      • Rodijk-Olthuis D.
      • et al.
      Psoriasis-associated late cornified envelope (LCE) proteins have antibacterial activity.
      utilized 3D reconstructed epidermis from human wt/wt or LCE3B/C-del primary keratinocytes. Interestingly, there was no observed difference between wt/wt and LCE3B/C-del epidermis in transepidermal water loss or penetration of hydrophilic and hydrophobic tracers that would indicate inside-out or outside-in barrier dysfunction, respectively (
      • Niehues H.
      • Tsoi L.C.
      • van der Krieken D.A.
      • Jansen P.A.M.
      • Oortveld M.A.W.
      • Rodijk-Olthuis D.
      • et al.
      Psoriasis-associated late cornified envelope (LCE) proteins have antibacterial activity.
      ). This led the investigators to search for an alternative functional role for these proteins.

      LCE3 proteins function as antimicrobial peptides

      Antimicrobial peptides (AMPs) are small, typically cationic peptides that exhibit broad-spectrum activity against bacteria, fungi, and viruses, and also promote cell migration, wound healing, cytokine production, and skin barrier function (
      • Gallo R.L.
      • Hooper L.V.
      Epithelial antimicrobial defence of the skin and intestine.
      ). The major known AMPs in skin include defensins, cathelicidin, S100 proteins, ribonucleases (RNases), and dermcidin, among others. In human skin, some AMPs are constitutively expressed, whereas others are induced on injury, infection, or inflammation. Interestingly, the LCE3 proteins resemble AMPs in that they are cationic and have a low molecular weight. This prompted
      • Niehues H.
      • Tsoi L.C.
      • van der Krieken D.A.
      • Jansen P.A.M.
      • Oortveld M.A.W.
      • Rodijk-Olthuis D.
      • et al.
      Psoriasis-associated late cornified envelope (LCE) proteins have antibacterial activity.
      to investigate whether LCE3 proteins had antimicrobial activity. They demonstrated that the LCE3 family proteins displayed broad-spectrum antimicrobial activity (with LCE3A being the most potent) against Gram-positive, Gram-negative, and anaerobic bacteria, including, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Corynebacterium aurimucosum, Staphylococcus capitis, Staphylococcus epidermis, Streptococcus pyogenes, and Propionibacterium acnes but not Staphylococcus aureus. Thus, a previously unknown antimicrobial function for the epidermal-derived LCE3 proteins was identified.

      Perspectives of the role of LCE3 proteins in psoriasis and beyond

      The skin microbiome contributes to normal immune development and maintenance of the skin barrier, but it also can be the source of pathogenic inflammation and infection (
      • Grice E.A.
      • Segre J.A.
      The skin microbiome.
      ). In the present study, the observed increase in expression of the antimicrobial LCE3 proteins in psoriasis suggests that they may function like other AMPs that are also increased in psoriasis, such as β-defensins, cathelicidin, and psoriasin (
      • Gallo R.L.
      • Nakatsuji T.
      Microbial symbiosis with the innate immune defense system of the skin.
      ). The collective antimicrobial activity of these AMPs alters the skin microbiome, and this dysbiosis, along with the proinflammatory effects of AMPs (e.g., keratinocyte proliferation, cytokine production, immune cell chemotactic activity), contributes to psoriasis pathogenesis (
      • Gallo R.L.
      • Nakatsuji T.
      Microbial symbiosis with the innate immune defense system of the skin.
      ). In particular, aberrant baseline expression of LCE3A was found in the normal skin of patients with the psoriasis-related LCE3B/C-del compared with wt/wt, suggesting that the selectively increased expression of LCE3A might be an important factor that impacts dysbiosis and cutaneous inflammation that contributes to the development of psoriasis.
      There are several unanswered questions. It is unclear why the LCE3B/C-del is found at higher frequency (62−64%) in East-Asian, South-Asian, and European populations than African populations (37%). The authors propose that this mutation might have had a selection advantage for out-of-African populations. Such a possibility could occur if the baseline overexpression of LCE3A in response to the LCE3B/C-del mutation led to enhanced protection from pathogens, albeit at the expense of increasing the risk of psoriasis. In addition, an explanation for the epistatic interaction between the LCE3B/C-del mutation and HLA-C*06:02 as risk factors for psoriasis is not yet apparent. However, it is possible that overexpression of LCE3 results in an altered self or microbial antigen exposure that promotes HLA-C*06:02 restricted immune responses. Finally, LCE3 proteins are also expressed in the oral epithelium, and the consequences of their antimicrobial activity as well as the LCE3B/C-del mutation are unknown at this anatomical site. These possibilities and additional functional roles of LCE3 proteins will require future investigation. Nonetheless, the determination that LCE3 proteins function as AMPs rather than in maintaining the epidermal barrier provides important new insights into the pathogenesis of psoriasis and suggests a novel physiologic role for LCE3 proteins in cutaneous host defense.

      Conflict of Interest

      LSM has received grant support from MedImmune, Regeneron Pharmaceuticals, Pfizer, and Moderna Therapeutics and is a shareholder of Noveome Biotherapeutics. The rest of the authors state no conflict of interest.

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      Linked Article

      • Psoriasis-Associated Late Cornified Envelope (LCE) Proteins Have Antibacterial Activity
        Journal of Investigative DermatologyVol. 137Issue 11
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          Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06.
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