Advertisement
Journal of Investigative Dermatology Home

A Spectrum of Skin Disease: How Staphylococcus aureus Colonization, Barrier Dysfunction, and Cytokines Shape the Skin

      Cytokines are key mediators of skin homeostasis and disease through their effects on keratinocytes, skin barrier integrity, immune activation, and microbial ecology.
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      suggest that the IFN signature in lupus erythematosus (LE) alters expression of epithelial barrier and adhesin genes, which, in turn, promotes Staphylococcus aureus colonization. This work highlights the need to better understand both barrier function and S. aureus colonization in LE, two new potential therapeutic targets for the treatment of LE.
      Neutrophils decrease skin protection against S. aureus in specific conditions by contact-free mechanisms.
      Psoriasis (PS), atopic dermatitis (AD), and cutaneous lupus erythematosus (LE) represent a unique spectrum of skin diseases based on the characteristics of barrier dysfunction, Staphylococcus aureus colonization, and cutaneous cytokine profiles. These features are thought to contribute to disease onset and exacerbations in a feed-forward loop, but without real clarity on which is primary or their relative importance.
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      investigate the effects of type I IFNs on S. aureus colonization and epithelial barrier gene expression in LE. This study, together with our current understanding of epidermal barrier function and S. aureus colonization in PS and AD, places LE in the center of this barrier disruption and S. aureus colonization continuum (Table 1).
      Table 1Unifying and Distinguishing Features of Three Common Inflammatory Skin Disorders
      DiseaseSkin S. aureus (culture)Skin S. aureus Adhesin ExpressionReduced Skin Barrier Gene Expression
      We have included only epithelial genes whose reduced expression has been shown to affect barrier function.
      NL Skin Barrier Dysfunction (TEWL)Skin

      Cytokines
      Skin Lesion

      Location
      Atopic dermatitisL > NL
      Weidinger et al., 2018.
      (>90%)
      Yes
      Cho et al., 2001.
      ,
      Cho, Strickland et al. 2001.
      (FGG & FN1)
      FLG, FLG2,

      CLDN1, CLDN4, CLDN8, CLDN23
      Weidinger et al., 2018.
      ,
      Brewer et al., 2019.
      Yes
      Weidinger et al., 2018.
      ,
      Brewer et al., 2019.
      ,
      De Benedetto et al., 2011.
      IL-4, IL-13, IL-22, IFNγFlexors
      LupusL (50%)
      Sirobhushanam et al., 2020.


      NL (0%)
      Yes
      Sirobhushanam et al., 2020.
      (ITGA5)
      DSG1, CLDN1, CLDN11, FLG, FLG2
      Sirobhushanam et al., 2020.
      ,
      Polivka et al., 2018.
      Table 1.
      Figure 4.
      NDtype I IFNs, IL-12, IL-17, IL-23UV exposed
      PsoriasisL (0%)
      Sirobhushanam et al., 2020.
      NDNot well studied
      Visconti et al., 2015.
      Normal
      Darlenski et al., 2018.
      TNFα, IFNα, IL-12, IL-17,

      IL-22, IL-23
      Guttman-Yassky et al., 2011.
      Extensors palms & soles
      Abbreviations: CLDN, claudin; DSG, desmoglein; FGG, fibrinogen, FLG, filaggrin; FN1, fibronectin; ITGA5, integrin subunit alpha 5; L, lesional; ND, not done; NL, nonlesional; S. aureus, Staphylococcus aureus; TEWL, transepidermal water loss.
      Red text indicates unifying features.
      1 We have included only epithelial genes whose reduced expression has been shown to affect barrier function.
      2
      • Weidinger S.
      • Beck L.A.
      • Bieber T.
      • Kabashima K.
      • Irvine A.D.
      Atopic dermatitis.
      .
      3
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      .
      4
      • Cho S.H.
      • Strickland I.
      • Boguniewicz M.
      • Leung D.Y.
      Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin.
      ,
      • Cho S.H.
      • Strickland I.
      • Tomkinson A.
      • Fehringer A.P.
      • Gelfand E.W.
      • Leung D.Y.
      Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
      .
      5
      • Cho S.H.
      • Strickland I.
      • Boguniewicz M.
      • Leung D.Y.
      Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin.
      ,
      • Cho S.H.
      • Strickland I.
      • Tomkinson A.
      • Fehringer A.P.
      • Gelfand E.W.
      • Leung D.Y.
      Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
      .
      6
      • Brewer M.G.
      • Yoshida T.
      • Kuo F.I.
      • Fridy S.
      • Beck L.A.
      • De Benedetto A.
      Antagonistic effects of IL-4 on IL-17A-Mediated enhancement of epidermal tight junction function.
      .
      7
      • De Benedetto A.
      • Rafaels N.M.
      • McGirt L.Y.
      • Ivanov A.I.
      • Georas S.N.
      • Cheadle C.
      • et al.
      Tight junction defects in patients with atopic dermatitis.
      .
      8
      • Darlenski R.
      • Hristakieva E.
      • Aydin U.
      • Gancheva D.
      • Gancheva T.
      • Zheleva A.
      • et al.
      Epidermal barrier and oxidative stress parameters improve during in 311nm narrow band UVB phototherapy of plaque type psoriasis.
      .
      9
      • Visconti B.
      • Paolino G.
      • Carotti S.
      • Pendolino A.L.
      • Morini S.
      • Richetta A.G.
      • et al.
      Immunohistochemical expression of VDR is associated with reduced integrity of tight junction complex in psoriatic skin.
      .
      10
      • Guttman-Yassky E.
      • Nograles K.E.
      • Krueger J.G.
      Contrasting pathogenesis of atopic dermatitis and psoriasis--part II: immune cell subsets and therapeutic concepts.
      .
      11
      • Polivka L.
      • Hadj-Rabia S.
      • Bal E.
      • Leclerc-Mercier S.
      • Madrange M.
      • Hamel Y.
      • et al.
      Epithelial barrier dysfunction in desmoglein-1 deficiency.
      .
      12 Table 1.
      13 Figure 4.

       S. aureus skin colonization

      S. aureus skin colonization can play a significant role in the onset, progression, and severity of skin disease. Numerous studies have shown that >90% of patients with AD are colonized with S. aureus, which contrasts with ∼20% of healthy controls and rare individuals with PS (
      • Otto M.
      Staphylococcus colonization of the skin and antimicrobial peptides.
      ). We recently demonstrated that subjects with AD colonized with S. aureus have more severe disease, as measured by the Eczema Area and Severity Index; greater skin barrier disruption, as measured by increased transepidermal water loss (TEWL); and more type 2 immune deviation, as measured by elevations in serum total IgE, CCL17 levels, and absolute eosinophil counts (
      • Simpson E.L.
      • Villarreal M.
      • Jepson B.
      • Rafaels N.
      • David G.
      • Hanifin J.
      • et al.
      Patients with atopic dermatitis colonized with Staphylococcus aureus Have a distinct phenotype and endotype.
      ).
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      evaluate the frequency of S. aureus skin colonization in a small cohort of patients with PS and a much larger sample of patients with LE using routine culture techniques and PCR validation. They observed a modest increase in the percentage of patients with LE who were colonized with S. aureus, an enhanced epithelial expression of S. aureus adhesins (IGA5 and FN1), and a greater S. aureus adhesion to LE keratinocytes.

       Psoriasis

      PS, in contrast to AD and LE, is a largely IL-17–driven disease. Although this IL-17 skewing is relevant for the pathogenesis of a number of autoimmune and inflammatory disorders, it is also recognized as an important component of host defense and repair following infections with S. aureus (
      • Otto M.
      Staphylococcus colonization of the skin and antimicrobial peptides.
      ). IL-17 is thought to have a number of protective roles in the skin, including enhancing production of antimicrobial peptides, such as lipocalin 2 and β-defensin, as well as neutrophil recruitment (
      • Guttman-Yassky E.
      • Krueger J.G.
      Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?.
      ). More recently, IL-17A has also been shown to enhance tight junction (TJ) barrier function in primary human keratinocytes (
      • Brewer M.G.
      • Yoshida T.
      • Kuo F.I.
      • Fridy S.
      • Beck L.A.
      • De Benedetto A.
      Antagonistic effects of IL-4 on IL-17A-Mediated enhancement of epidermal tight junction function.
      ). Collectively, these actions likely contribute to the observation made by
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      that none of their six subjects with PS were colonized with S. aureus.

       Atopic Dermatitis

      AD is characterized by type 2 immunity, epidermal barrier disruption, and S. aureus colonization (
      • Weidinger S.
      • Beck L.A.
      • Bieber T.
      • Kabashima K.
      • Irvine A.D.
      Atopic dermatitis.
      ). Barrier dysfunction is thought to be the consequence of reduced expression of stratum corneum (SC) and TJ structural proteins, an imbalance of proteases and protease inhibitors, and altered lipid composition and organization. Epidermal barrier disruption promotes the release of alarmins such as TSLP, IL-25, and IL-33 that activate innate lymphoid cell type 2 cells and promote the recruitment of T helper type 2 (Th2) cells by inducing the release of the chemokines CCL17 and CCL20. The type 2 cytokines IL-4 and IL-13 have been shown to increase keratinocyte sensitivity to S. aureus toxins, suppress antimicrobial peptides, and promote S. aureus attachment by enhancing expression of fibrinogen and fibronectin (
      • Cho S.H.
      • Strickland I.
      • Boguniewicz M.
      • Leung D.Y.
      Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin.
      ,
      • Cho S.H.
      • Strickland I.
      • Tomkinson A.
      • Fehringer A.P.
      • Gelfand E.W.
      • Leung D.Y.
      Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
      ,
      • Weidinger S.
      • Beck L.A.
      • Bieber T.
      • Kabashima K.
      • Irvine A.D.
      Atopic dermatitis.
      ). Collectively, these effects are thought to explain the high rates of S. aureus colonization in this disease, which arguably fuels a vicious cycle of barrier disruption and inflammation, ultimately leading to greater disease severity.

       Lupus Erythematosus

      Whereas PS is characterized by increased skin barrier function with decreased bacterial colonization and AD by the opposite, little was known about skin barrier proteins and bacterial colonization in the skin of patients with lupus. LE is characterized by an elevated type I IFN signature, both in the skin and systemically.
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      suggest that, similar to AD, patients with LE may have a feedback loop whereby type I IFNs alter the expression of epidermal barrier genes and S. aureus adhesins, thereby promoting S. aureus skin colonization, which drives further cytokine expression. This hypothesis would suggest that patients with LE with S. aureus colonization would have more severe systemic disease, which should be addressed in future studies.
      The effect of the cytokine milieu on barrier function in LE appears to be complex. As in AD, FN1 expression is increased and β-defensins are decreased in LE skin lesions as compared with controls (Figure 4), which would increase the likelihood of chronic S. aureus colonization. These expression differences are further enhanced in AD by the actions of Th2 cytokines (IL-4 and IL-13). However, the opposite effect was observed in IFNα-stimulated keratinocytes (Figures 2 and 4). This suggests that other cytokines that are present in LE skin are likely to be responsible for S. aureus colonization. IL-13, which has been shown to be elevated in LE, may contribute to the observed gene expression changes and ultimately S. aureus skin colonization observed in half of patients with LE (
      • Morimoto S.
      • Tokano Y.
      • Kaneko H.
      • Nozawa K.
      • Amano H.
      • Hashimoto H.
      The increased interleukin-13 in patients with systemic lupus erythematosus: relations to other Th1-, Th2-related cytokines and clinical findings.
      ).
      The epidermal barrier has been studied in AD at the genetic, mRNA, protein, and functional levels. Null mutations in SC barrier genes such as FLG and FLG2 predispose individuals to development of AD, but their precise effects on barrier function and S. aureus colonization are still disputed (
      • Hansmann B.
      • Ahrens K.
      • Wu Z.
      • Proksch E.
      • Meyer-Hoffert U.
      • Schröder J.M.
      Murine filaggrin-2 is involved in epithelial barrier function and down-regulated in metabolically induced skin barrier dysfunction.
      ,
      • Kawasaki H.
      • Nagao K.
      • Kubo A.
      • Hata T.
      • Shimizu A.
      • Mizuno H.
      • et al.
      Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.
      ,
      • Weidinger S.
      • Beck L.A.
      • Bieber T.
      • Kabashima K.
      • Irvine A.D.
      Atopic dermatitis.
      ). The allergen sensitization that is characteristic of patients with AD is thought to be due to disruption of both SC and TJ barriers, which is supported by the reduced expression of a number of TJ proteins (CLDN-1, -4, -8, and -23). Similar observations have been made in canine AD (
      • Altunbulakli C.
      • Reiger M.
      • Neumann A.U.
      • Garzorz-Stark N.
      • Fleming M.
      • Huelpuesch C.
      • et al.
      Relations between epidermal barrier dysregulation and Staphylococcus species-dominated microbiome dysbiosis in patients with atopic dermatitis.
      ,
      • De Benedetto A.
      • Rafaels N.M.
      • McGirt L.Y.
      • Ivanov A.I.
      • Georas S.N.
      • Cheadle C.
      • et al.
      Tight junction defects in patients with atopic dermatitis.
      ,
      • Kim H.J.
      • Cronin M.
      • Ahrens K.
      • Papastavros V.
      • Santoro D.
      • Marsella R.
      A comparative study of epidermal tight junction proteins in a dog model of atopic dermatitis.
      ).
      • Sirobhushanam S.
      • Parsa N.
      • Reed T.J.
      • Berthier C.C.
      • Sarkar M.K.
      • Hile G.A.
      • et al.
      Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
      show that mRNA expression of several SC and TJ barrier proteins is decreased in skin biopsies or LE keratinocytes, but only a few of these proteins have been shown to affect barrier function (Table 1 and Figure 4; FLG, CLDN-1, CLDN-11, DSG1) (
      • Tamura A.
      • Tsukita S.
      Paracellular barrier and channel functions of TJ claudins in organizing biological systems: advances in the field of barriology revealed in knockout mice.
      ). Unfortunately, this study did not determine if these alterations in barrier gene expression were reflected in physiological measures of epidermal barrier function in patients with LE (in vivo) or in their keratinocytes (in vitro). Future studies will need to evaluate whether reductions in these barrier genes increase TEWL measurements in patients with LE or diminish transepithelial electrical resistance in LE keratinocytes propagated ex vivo. Such studies may highlight the potential importance of addressing skin barrier disturbance as a new therapeutic strategy for patients with LE.

       Future therapeutic approaches

      The authors previously demonstrated the importance of IFNκ in cutaneous LE pathogenesis (
      • Sarkar M.K.
      • Hile G.A.
      • Tsoi L.C.
      • Xing X.
      • Liu J.
      • Liang Y.
      • et al.
      Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.
      ). The three IFN types, type I IFN (e.g., IFNα and IFNκ), type II (IFNγ), and type III (IFNλ), should be explored to define their relative importance in epithelial barrier integrity, epithelial innate immune responses, expression of S. aureus adhesins, and ultimately in S. aureus colonization. Baricitinib, which is an oral selective Janus kinase (Jak) 1 and Jak2 inhibitor that improves the signs and symptoms of LE, was shown to reverse the increased S. aureus adhesion observed in IFNα-stimulated keratinocytes (Figure 3) (
      • Wallace D.J.
      • Furie R.A.
      • Tanaka Y.
      • Kalunian K.C.
      • Mosca M.
      • Petri M.A.
      • et al.
      Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial.
      ). A more targeted therapy to directly address the effect of type I IFNs on barrier function and S. aureus colonization in patients with LE would be anifrolumab, which is a fully human monoclonal antibody that binds to subunit 1 of the type I IFN receptor. Anifrolumab has recently been shown to be effective in LE (
      • Morand E.F.
      • Furie R.
      • Tanaka Y.
      • Bruce I.N.
      • Askanase A.D.
      • Richez C.
      • et al.
      Trial of anifrolumab in active systemic lupus erythematosus.
      ).
      Ustekinumab, a monoclonal antibody targeting IL-12 and IL-23 that is FDA-approved to treat PS, has also shown some benefit for the treatment of LE (
      • van Vollenhoven R.F.
      • Hahn B.H.
      • Tsokos G.C.
      • Wagner C.L.
      • Lipsky P.
      • Touma Z.
      • et al.
      Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study.
      ). This might seem surprising based on its inhibition of the IL-17 pathway, which one might predict would further aggravate skin barrier dysfunction and promote S. aureus colonization in LE (
      • Brewer M.G.
      • Yoshida T.
      • Kuo F.I.
      • Fridy S.
      • Beck L.A.
      • De Benedetto A.
      Antagonistic effects of IL-4 on IL-17A-Mediated enhancement of epidermal tight junction function.
      ). Although IL-17 has been shown to be modestly elevated in LE, there is not much evidence that this is relevant for LE pathogenesis (
      • Martin J.C.
      • Baeten D.L.
      • Josien R.
      Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus.
      ). Therefore, one might assume that ustekinumab is improving LE primarily via its actions on IL-12 blockade and the inhibitory effect this has on the T helper type 1 response.
      New therapeutic approaches to LE, both cutaneous and systemic, are needed as only one medication has been FDA-approved for LE in the past 60 years. By comparison, great strides have been made in the development of targeted and safe treatments for PS and recently for AD as well. This paper highlights a new hypothesis, namely that cutaneous colonization with S. aureus may play a role in LE pathogenesis. The importance of S. aureus colonization in systemic LE as either a driver of type I IFNs or as a consequence of skin barrier disruption (or both) needs to be established. This study also suggests that there is much more to be done to understand the complex relationship between inflammatory skin diseases and cutaneous microbial ecology.

      Conflict of Interest

      LAB is a consultant for Abbvie, Allakos, Astra-Zeneca, Connect Biopharma, LEO Pharma, Lilly, Novartis, Pfizer, Regeneron, Sanofi, UCB, and Vimalan. She has been an investigator for Abbvie, LEO Pharma, Pfizer, and Regeneron, and she owns Pfizer and Medtronics stock. CTR is an investigator for LEO Pharma. MCM has no conflict of interest.

      ORCIDs

      Christopher T. Richardson: https://orcid.org/0000-0002-7692-1768

      Acknowledgments

      MCM is supported by the National Institute of Allergy and Infectious Diseases ( T32 AI118689 ). LAB is supported by the National Institute of Allergy and Infectious Diseases ( U19AI117673 ).

      References

        • Altunbulakli C.
        • Reiger M.
        • Neumann A.U.
        • Garzorz-Stark N.
        • Fleming M.
        • Huelpuesch C.
        • et al.
        Relations between epidermal barrier dysregulation and Staphylococcus species-dominated microbiome dysbiosis in patients with atopic dermatitis.
        J Allergy Clin Immunol. 2018; 142: 1643-1647.e12
        • Brewer M.G.
        • Yoshida T.
        • Kuo F.I.
        • Fridy S.
        • Beck L.A.
        • De Benedetto A.
        Antagonistic effects of IL-4 on IL-17A-Mediated enhancement of epidermal tight junction function.
        Int J Mol Sci. 2019; 20
        • Cho S.H.
        • Strickland I.
        • Boguniewicz M.
        • Leung D.Y.
        Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin.
        J Allergy Clin Immunol. 2001; 108: 269-274
        • Cho S.H.
        • Strickland I.
        • Tomkinson A.
        • Fehringer A.P.
        • Gelfand E.W.
        • Leung D.Y.
        Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
        J Invest Dermatol. 2001; 116: 658-663
        • Darlenski R.
        • Hristakieva E.
        • Aydin U.
        • Gancheva D.
        • Gancheva T.
        • Zheleva A.
        • et al.
        Epidermal barrier and oxidative stress parameters improve during in 311nm narrow band UVB phototherapy of plaque type psoriasis.
        J Dermatol Sci. 2018; 91: 28-34
        • De Benedetto A.
        • Rafaels N.M.
        • McGirt L.Y.
        • Ivanov A.I.
        • Georas S.N.
        • Cheadle C.
        • et al.
        Tight junction defects in patients with atopic dermatitis.
        J Allergy Clin Immunol. 2011; 127: 773-786.e7
        • Guttman-Yassky E.
        • Krueger J.G.
        Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?.
        Curr Opin Immunol. 2017; 48: 68-73
        • Guttman-Yassky E.
        • Nograles K.E.
        • Krueger J.G.
        Contrasting pathogenesis of atopic dermatitis and psoriasis--part II: immune cell subsets and therapeutic concepts.
        J Allergy Clin Immunol. 2011; 127: 1420-1432
        • Hansmann B.
        • Ahrens K.
        • Wu Z.
        • Proksch E.
        • Meyer-Hoffert U.
        • Schröder J.M.
        Murine filaggrin-2 is involved in epithelial barrier function and down-regulated in metabolically induced skin barrier dysfunction.
        Exp Dermatol. 2012; 21: 271-276
        • Kawasaki H.
        • Nagao K.
        • Kubo A.
        • Hata T.
        • Shimizu A.
        • Mizuno H.
        • et al.
        Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.
        J Allergy Clin Immunol. 2012; 129: 1538-1546.e6
        • Kim H.J.
        • Cronin M.
        • Ahrens K.
        • Papastavros V.
        • Santoro D.
        • Marsella R.
        A comparative study of epidermal tight junction proteins in a dog model of atopic dermatitis.
        Vet Dermatol. 2016; 27 (40–e11)
        • Martin J.C.
        • Baeten D.L.
        • Josien R.
        Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus.
        Clin Immunol. 2014; 154: 1-12
        • Morand E.F.
        • Furie R.
        • Tanaka Y.
        • Bruce I.N.
        • Askanase A.D.
        • Richez C.
        • et al.
        Trial of anifrolumab in active systemic lupus erythematosus.
        N Engl J Med. 2020; 382: 211-221
        • Morimoto S.
        • Tokano Y.
        • Kaneko H.
        • Nozawa K.
        • Amano H.
        • Hashimoto H.
        The increased interleukin-13 in patients with systemic lupus erythematosus: relations to other Th1-, Th2-related cytokines and clinical findings.
        Autoimmunity. 2001; 34: 19-25
        • Otto M.
        Staphylococcus colonization of the skin and antimicrobial peptides.
        Expert Rev Dermatol. 2010; 5: 183-195
        • Polivka L.
        • Hadj-Rabia S.
        • Bal E.
        • Leclerc-Mercier S.
        • Madrange M.
        • Hamel Y.
        • et al.
        Epithelial barrier dysfunction in desmoglein-1 deficiency.
        J Allergy Clin Immunol. 2018; 142 (e707): 702
        • Sarkar M.K.
        • Hile G.A.
        • Tsoi L.C.
        • Xing X.
        • Liu J.
        • Liang Y.
        • et al.
        Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.
        Ann Rheum Dis. 2018; 77: 1653-1664
        • Simpson E.L.
        • Villarreal M.
        • Jepson B.
        • Rafaels N.
        • David G.
        • Hanifin J.
        • et al.
        Patients with atopic dermatitis colonized with Staphylococcus aureus Have a distinct phenotype and endotype.
        J Invest Dermatol. 2018; 138: 2224-2233
        • Sirobhushanam S.
        • Parsa N.
        • Reed T.J.
        • Berthier C.C.
        • Sarkar M.K.
        • Hile G.A.
        • et al.
        Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption.
        J Invest Dermatol. 2020; 140: 1066-1074
        • Tamura A.
        • Tsukita S.
        Paracellular barrier and channel functions of TJ claudins in organizing biological systems: advances in the field of barriology revealed in knockout mice.
        Semin Cell Dev Biol. 2014; 36: 177-185
        • van Vollenhoven R.F.
        • Hahn B.H.
        • Tsokos G.C.
        • Wagner C.L.
        • Lipsky P.
        • Touma Z.
        • et al.
        Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study.
        Lancet. 2018; 392: 1330-1339
        • Visconti B.
        • Paolino G.
        • Carotti S.
        • Pendolino A.L.
        • Morini S.
        • Richetta A.G.
        • et al.
        Immunohistochemical expression of VDR is associated with reduced integrity of tight junction complex in psoriatic skin.
        J Eur Acad Dermatol Venereol. 2015; 29: 2038-2042
        • Wallace D.J.
        • Furie R.A.
        • Tanaka Y.
        • Kalunian K.C.
        • Mosca M.
        • Petri M.A.
        • et al.
        Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial.
        Lancet. 2018; 392: 222-231
        • Weidinger S.
        • Beck L.A.
        • Bieber T.
        • Kabashima K.
        • Irvine A.D.
        Atopic dermatitis.
        Nat Rev Dis Primers. 2018; 4: 1

      Linked Article

      • Staphylococcus aureus Colonization Is Increased on Lupus Skin Lesions and Is Promoted by IFN-Mediated Barrier Disruption
        Journal of Investigative DermatologyVol. 140Issue 5
        • Preview
          Cutaneous inflammation is recurrent in systemic lupus erythematosus (SLE), yet mechanisms that drive cutaneous inflammation in SLE are not well defined. Type I IFNs are elevated in nonlesional SLE skin and promote inflammatory responses. Staphylococcus aureus, known to induce IFN production, could play a role in cutaneous inflammation in SLE. We show here that active cutaneous lupus erythematosus lesions are highly colonized (∼50%) by S. aureus. To define the impact of IFNs on S. aureus colonization, we examined the effects of type I and type II IFNs on S. aureus adherence and invasion.
        • Full-Text
        • PDF
        Open Archive