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Chemokines in the Pathogenesis of Lichenoid Tissue Reactions

      Clinical manifestations of lichenoid tissue reactions are heterogenous and include the cutaneous lupus erythematosus and lichen planus. Lichenoid tissue reactions are characterized by epidermal basal-cell damage and a variable subepithelial inflammatory infiltrate including cytotoxic TH1 cells and plasmacytoid dendritic cells. Here, we summarize the current knowledge of the role of chemokines in the pathophysiology of lichenoid tissue reactions and propose mechanisms by which recruitment and local activation of cytotoxic TH1 cells and plasmacytoid dendritic cells may result in initiation and amplification of lichen planus and cutaneous lupus erythematosus.

      Abbreviations

      DC
      dendritic cell
      LE
      lupus erythematosus
      LP
      lichen planus
      LTR
      lichenoid tissue reaction
      pDC
      plasmacytoid dendritic cell
      TLR
      toll-like receptor
      Treg
      regulatory T cell

      Introduction

      Chemokines are small, secreted, cytokine-like proteins that mediate directional migration and critically regulate organ-specific homing of leukocyte subsets (
      • Butcher E.C.
      • Picker L.J.
      Lymphocyte homing and homeostasis.
      ;
      • Zlotnik A.
      • Yoshie O.
      Chemokines: a new classification system and their role in immunity.
      ). Most chemokines have four characteristic cysteines. Depending on the motive displayed by the first two cysteines, chemokines have been classified into four subclasses (families): CC, CXC, C, and CX3C chemokines (
      • Zlotnik A.
      • Yoshie O.
      Chemokines: a new classification system and their role in immunity.
      ). The chemokine XCL1/lymphotactin represents a structural exception to this system, displaying solely one-cysteine residues. Chemokines mediate a broad range of biological functions, such as leukocyte recruitment, angiogenesis, wound healing, and metastasis by binding to their specific receptors, which belong to the superfamily of G-protein-coupled receptors with seven transmembrane domains (
      • Strieter R.M.
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      • Burdick M.D.
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      The functional role of the ELR motif in CXC chemokine-mediated angiogenesis.
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      The biology of chemokines and their receptors.
      ;
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      • Soto H.
      • Ge N.
      • Catron D.
      • Buchanan M.E.
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      Involvement of chemokine receptors in breast cancer metastasis.
      ;
      • Hiasa K.
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      • Zhao Q.
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      Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization.
      ). So far, 46 ligands binding to 19 human chemokine receptors have been identified, designated as CC, CXC, XC, or CX3C receptors (
      • Zlotnik A.
      • Yoshie O.
      • Nomiyama H.
      The chemokine and chemokine receptor superfamilies and their molecular evolution.
      ).
      Chemokines can be subdivided into homeostatic and inflammatory chemokines. The tissue- or organ-specific expressions of homeostatic chemokines confer defined functionality such as cell migration. In contrast, the cell-type-specific expression of inflammatory chemokines is dependent on adequate stimulation (
      • Zlotnik A.
      • Yoshie O.
      Chemokines: a new classification system and their role in immunity.
      ). Interestingly, homeostatic chemokines and inflammatory chemokines have been shown to cooperate synergistically in the recruitment of memory T cells (
      • Vanbervliet B.
      • Bendriss-Vermare N.
      • Massacrier C.
      • Homey B.
      • de Bouteiller O.
      • Briere F.
      • et al.
      The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12.
      ;
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). In recent years, compelling evidence has grown supporting the involvement of chemokines in the pathogenesis of lichenoid tissue reactions (LTRs;
      • Spandau U.
      • Toksoy A.
      • Goebeler M.
      • Brocker E.B.
      • Gillitzer R.
      MIG is a dominant lymphocyte-attractant chemokine in lichen planus lesions.
      ;
      • Meller S.
      • Lauerma A.I.
      • Kopp F.M.
      • Winterberg F.
      • Anthoni M.
      • Muller A.
      • et al.
      Chemokine responses distinguish chemical-induced allergic from irritant skin inflammation: memory T cells make the difference.
      ; Figure 1). LTR comprises many clinically heterogenous skin diseases and are defined histologically by epidermal basal-cell damage and a band-like lymphocytic infiltration in the upper dermis. The pathogenesis of LTRs is currently viewed as an attack and destruction of the basal epidermal layer by autoreactive cytotoxic T cells secreting a TH1-type cytokine profile (
      • Iijima W.
      • Ohtani H.
      • Nakayama T.
      • Sugawara Y.
      • Sato E.
      • Nagura H.
      • et al.
      Infiltrating CD8+ T cells in oral lichen planus predominantly express CCR5 and CXCR3 and carry respective chemokine ligands RANTES/CCL5 and IP-10/CXCL10 in their cytolytic granules: a potential self-recruiting mechanism.
      ;
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ;
      • Wenzel J.
      • Uerlich M.
      • Worrenkamper E.
      • Freutel S.
      • Bieber T.
      • Tuting T.
      Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA.
      ). Recent evidence suggests that plasmacytoid dendritic cells (pDCs) also infiltrate the subepidermal compartment of LTRs and are activated to produce type I IFNs, an early key innate event that unleashes the cytotoxic T-cell response and the formation of LTR (
      • Fitzgerald-Bocarsly P.
      Human natural interferon-alpha producing cells.
      ;
      • Farkas L.
      • Beiske K.
      • Lund-Johansen F.
      • Brandtzaeg P.
      • Jahnsen F.L.
      Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions.
      ;
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ;
      • Santoro A.
      • Majorana A.
      • Roversi L.
      • Gentili F.
      • Marrelli S.
      • Vermi W.
      • et al.
      Recruitment of dendritic cells in oral lichen planus.
      ;
      • de Vries H.J.
      • van Marle J.
      • Teunissen M.B.
      • Picavet D.
      • Zorgdrager F.
      • Bos J.D.
      • et al.
      Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells.
      ). Furthermore, recent findings suggest that a distinct set of chemokines is preferentially expressed and mediates the recruitment of pathogenic leukocyte subsets in LTRs. In contrast to other inflammatory skin diseases such as atopic dermatitis or psoriasis vulgaris, LTRs are characterized by the upregulation of inflammatory CXCR3 ligands associated with the recruitment of both effector cytotoxic T cells and pDC (
      • Spandau U.
      • Toksoy A.
      • Goebeler M.
      • Brocker E.B.
      • Gillitzer R.
      MIG is a dominant lymphocyte-attractant chemokine in lichen planus lesions.
      ;
      • Homey B.
      • Dieu-Nosjean M.C.
      • Wiesenborn A.
      • Massacrier C.
      • Pin J.J.
      • Oldham E.
      • et al.
      Up-regulation of macrophage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis.
      ;
      • Iijima W.
      • Ohtani H.
      • Nakayama T.
      • Sugawara Y.
      • Sato E.
      • Nagura H.
      • et al.
      Infiltrating CD8+ T cells in oral lichen planus predominantly express CCR5 and CXCR3 and carry respective chemokine ligands RANTES/CCL5 and IP-10/CXCL10 in their cytolytic granules: a potential self-recruiting mechanism.
      ;
      • Gombert M.
      • Dieu-Nosjean M.C.
      • Winterberg F.
      • Bünemann E.
      • Kubitza R.C.
      • Da Cunha L.
      • et al.
      CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and langerhans-type dendritic cells to sites of atopic skin inflammation.
      ;
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ;
      • Wenzel J.
      • Schmidt R.
      • Proelss J.
      • Zahn S.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis.
      ,
      • Wenzel J.
      • Wiechert A.
      • Merkel C.
      • Bieber T.
      • Tuting T.
      IP10/CXCL10 CXCR3 interaction: a potential self-recruiting mechanism for cytotoxic lymphocytes in lichen sclerosus et atrophicus.
      ;
      • Piper K.P.
      • Horlock C.
      • Curnow S.J.
      • Arrazi J.
      • Nicholls S.
      • Mahendra P.
      • et al.
      CXCL10-CXCR3 interactions play an important role in the pathogenesis of acute graft-versus-host disease in the skin following allogeneic stem-cell transplantation.
      ). Cytotoxic CXCR3-positive T cells may sustain a cytolytic immune response in LTR (
      • De Panfilis G.
      CD8+ cytolytic T lymphocytes and the skin.
      ;
      • Sugerman P.B.
      • Satterwhite K.
      • Bigby M.
      Autocytotoxic T-cell clones in lichen planus.
      ;
      • Wenzel J.
      • Uerlich M.
      • Worrenkamper E.
      • Freutel S.
      • Bieber T.
      • Tuting T.
      Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA.
      ). Notably, atopic dermatitis or psoriasis vulgaris did not show comparable expression levels of CXCR3 ligands and are dominated by the expression of CCL1 and CCL20, respectively (
      • Homey B.
      • Dieu-Nosjean M.C.
      • Wiesenborn A.
      • Massacrier C.
      • Pin J.J.
      • Oldham E.
      • et al.
      Up-regulation of macrophage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis.
      ;
      • Gombert M.
      • Dieu-Nosjean M.C.
      • Winterberg F.
      • Bünemann E.
      • Kubitza R.C.
      • Da Cunha L.
      • et al.
      CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and langerhans-type dendritic cells to sites of atopic skin inflammation.
      ). Here, we summarize the current knowledge on the role of chemokines in the pathogenesis of LTRs and present a model for their involvement in the initiation and maintenance of pathogenic inflammation in lichen planus (LP) and cutaneous lupus erythematosus.
      Figure thumbnail gr1
      Figure 1Lichenoid tissue reaction (LTR). During the initiation of LTR, pDCs are activated by circulating immune complexes, viruses or by self-DNA/LL37 complexes induced during skin injury, leading to the abundant production of IFN-α. The IFN-α signal may represent an early event in the initiation of lichenoid skin reaction. IFN-α induces the production of CXCR3 ligands in structural cells of the skin and activates cytotoxic T cells secreting TH1 cytokines either directly or indirectly through activation of mDCs. Activated cytotoxic TH1 cells and pDCs amplify perpetuate the production of CXCR3 ligands through secretion of IFNs leading to additional recruitment of pDC and pathogenic T cells, and development of a LTR phenotype.

      Chemokines and Lichenoid Tissue Reactions

      Chemokines in the pathogenesis of cutaneous lupus erythematosus

      Cutaneous lupus erythematosus (LE) represents an autoimmune disease of unknown etiology (
      • Crowson A.N.
      • Magro C.
      The cutaneous pathology of lupus erythematosus: a review.
      ). Histologically, LE is characterized by apoptosis of keratinocytes and a band-like inflammatory infiltrate in superficial and/or deep compartments of the skin. Interestingly, LE patients often show a marked photosensitivity and cutaneous LE lesions often occur at sun-exposed sites. In vitro, UV-irradiated keratinocytes release potent chemoattractants for lymphocytes such as CCL5/Rantes, CCL20/MIP3α, CCL22/MDC, and CXCL8/IL-8 (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Furthermore, comprehensive analyses of chemokine expression demonstrated that UV-inducible chemokines such as CCL5 and CXCL8 are among the most differentially regulated chemokines in cutaneous LE suggesting a molecular signature of recent UV-induced injury (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Moreover, UV-induced apoptosis or necrosis of keratinocytes may promote the release of homeostatic chemokines (for example CCL27/CTACK) from epidermal stores into the dermis (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Recently, the skin-specific chemokine CCL27 has been shown to play an important role during the recruitment of CCR10-positive memory T cells into the skin (
      • Morales J.
      • Homey B.
      • Vicari A.P.
      • Hudak S.
      • Oldham E.
      • Hedrick J.
      • et al.
      CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells.
      ). This CC chemokine is abundantly and homeostatically produced by basal keratinocytes in healthy skin and CCL27 has been shown to bind with high affinity to extracellular matrix components and to impregnate the surface of dermal fibroblasts and endothelial cells (
      • Homey B.
      • Alenius H.
      • Muller A.
      • Soto H.
      • Bowman E.P.
      • Yuan W.
      • et al.
      CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.
      ). Skin specimens from patients with dermatitis solaris or, to a larger extent, early skin lesions of patients with LE undergoing diagnostic UV irradiation, show profound leakage of CCL27 from the basal epidermis into the papillary dermis with impregnation of CCL27 onto endothelial cells of the superficial plexus (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). On the contrary, advanced and chronic cutaneous LE displaying marked vacuolic degeneration of epidermal keratinocytes, are characterized by reduced amounts of CCL27 (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Hence, increased matrix-bound gradients of CCL27 following an UV-irradiation of the skin may represent an early event during the initiation of cutaneous LE, supporting the recruitment of a first wave of CCR10-positive skin-homing leukocyte subsets into the skin.
      Recent studies suggest that a TH1/TH2 imbalance with a predominance of TH1 cytokines, including IFN-γ, is of pathogenic importance in autoimmune diseases such as systemic lupus erythematosus (
      • Akahoshi M.
      • Nakashima H.
      • Tanaka Y.
      • Kohsaka T.
      • Nagano S.
      • Ohgami E.
      • et al.
      Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus.
      ;
      • Toro J.R.
      • Finlay D.
      • Dou X.
      • Zheng S.C.
      • LeBoit P.E.
      • Connolly M.K.
      Detection of type 1 cytokines in discoid lupus erythematosus.
      ;
      • Gomez D.
      • Correa P.A.
      • Gomez L.M.
      • Cadena J.
      • Molina J.F.
      • Anaya J.M.
      Th1/Th2 cytokines in patients with systemic lupus erythematosus: is tumor necrosis factor alpha protective?.
      ). It is well known that IFN-γ induces the expression of inflammatory chemokines such as CXCL9, CXCL10, and CXCL11. CXCR3, their matching receptor, is predominantly expressed on the surface of IFN-γ-producing TH1 cells (
      • Farber J.M.
      Mig and IP-10: CXC chemokines that target lymphocytes.
      ;
      • Cole K.E.
      • Strick C.A.
      • Paradis T.J.
      • Ogborne K.T.
      • Loetscher M.
      • Gladue R.P.
      • et al.
      Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3.
      ;
      • Kim C.H.
      • Rott L.
      • Kunkel E.J.
      • Genovese M.C.
      • Andrew D.P.
      • Wu L.
      • et al.
      Rules of chemokine receptor association with T cell polarization in vivo.
      ). In fact, lesions of cutaneous LE show a marked expression of these TH1-associated chemokines and their corresponding receptor CXCR3 compared to healthy skin (
      • Flier J.
      • Boorsma D.M.
      • van Beek P.J.
      • Nieboer C.
      • Stoof T.J.
      • Willemze R.
      • et al.
      Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation.
      ). In cutaneous LE, skin-infiltrating leukocytes in perivascular, subepidermal, and intraepidermal locations express CXCR3 in close anatomic proximity with the cells expressing CXCL9 and CXCL10 (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Moreover, human serum levels of CXCR3 ligands were upregulated in systemic lupus erythematosus and may reflect disease activity (
      • Narumi S.
      • Takeuchi T.
      • Kobayashi Y.
      • Konishi K.
      Serum levels of ifn-inducible PROTEIN-10 relating to the activity of systemic lupus erythematosus.
      ;
      • Bauer J.W.
      • Baechler E.C.
      • Petri M.
      • Batliwalla F.M.
      • Crawford D.
      • Ortmann W.A.
      • et al.
      Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus.
      ). Taken together, IFN-γ-inducible chemokines may play a role in cutaneous manifestations of LE, defining this entity as a putatively TH1-associated disease.
      Foxp3+ CD4+ CD25+ regulatory T cells (Treg) are critical for the regulation of host tolerance and suppression of pathological immune responses in autoimmune diseases and have been shown to be diminished in cutaneous LE (
      • Masteller E.L.
      • Tang Q.
      • Bluestone J.A.
      Antigen-specific regulatory T cells—ex vivo expansion and therapeutic potential.
      ;
      • Sakaguchi S.
      • Setoguchi R.
      • Yagi H.
      • Nomura T.
      Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in self-tolerance and autoimmune disease.
      ;
      • Franz B.
      • Fritzsching B.
      • Riehl A.
      • Oberle N.
      • Klemke C.D.
      • Sykora J.
      • et al.
      Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus.
      ). In contrast, lesional LP did not show any reduction in Treg in skin or circulation (
      • de Boer O.J.
      • van der Loos C.M.
      • Teeling P.
      • van der Wal A.C.
      • Teunissen M.B.
      Immunohistochemical analysis of regulatory T cell markers FOXP3 and GITR on CD4+CD25+ T cells in normal skin and inflammatory dermatoses.
      ). The chemokine repertoire of Treg in LTR remains largely unknown. Recently, Heller et al. associated the modulation of the local balance of the effector and regulatory T cells to CXCL10 (
      • Heller E.A.
      • Liu E.
      • Tager A.M.
      • Yuan Q.
      • Lin A.Y.
      • Ahluwalia N.
      • et al.
      Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells.
      ). Although overall T-cell accumulation in early atherosclerotic lesions in ApoE(-/-)/CXCL10(-/-) mice was reduced, Treg number and activity were enhanced, suggesting that the deficiency of CXCL10-mediated trafficking of CXCR3-expressing effector T cells leads to a pronounced regulatory phenotype (
      • Heller E.A.
      • Liu E.
      • Tager A.M.
      • Yuan Q.
      • Lin A.Y.
      • Ahluwalia N.
      • et al.
      Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells.
      ). Hence, the diminished numbers of Treg in cutaneous LE may partly be explained by the CXCL10-mediated modulation of the T-cell balance.
      Recently a central role of pDC in the pathogenesis of LE has been found (
      • Blanco P.
      • Palucka A.K.
      • Gill M.
      • Pascual V.
      • Banchereau J.
      Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.
      ;
      • Ronnblom L.
      • Alm G.V.
      A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus.
      ). pDCs have the unique capacity to rapidly produce huge amounts of IFN-α upon recognition of viral RNA and DNA through Toll-like receptor 7 (TLR7) and 9, respectively (
      • Liu Y.J.
      IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.
      ). Although pDCs are normally not able to respond to self-nucleic acids, in LE pDC become activated to produce type I IFNs by self-nucleic acids in complex with antibodies to DNA or nucleoproteins (
      • Ronnblom L.
      • Eloranta M.L.
      • Alm G.V.
      Role of natural interferon-alpha producing cells (plasmacytoid dendritic cells) in autoimmunity.
      ;
      • Barrat F.J.
      • Meeker T.
      • Gregorio J.
      • Chan J.H.
      • Uematsu S.
      • Akira S.
      • et al.
      Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus.
      ;
      • Means T.K.
      • Latz E.
      • Hayashi F.
      • Murali M.R.
      • Golenbock D.T.
      • Luster A.D.
      Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.
      ). These immune complexes trigger innate activation of pDC through TLR7 and 9 and lead to a sustained production of type I IFN that induce an unabated maturation of mDC and the activation of autoreactive T cells (
      • Blanco P.
      • Palucka A.K.
      • Gill M.
      • Pascual V.
      • Banchereau J.
      Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.
      ). In systemic lupus erythematosus the number of pDCs in the peripheral blood is decreased and their presence, accumulation, and activation in cutaneous lesions of LE have been reported (
      • Cederblad B.
      • Blomberg S.
      • Vallin H.
      • Perers A.
      • Alm G.V.
      • Ronnblom L.
      Patients with systemic lupus erythematosus have reduced numbers of circulating natural interferon-alpha- producing cells.
      ;
      • Blomberg S.
      • Eloranta M.L.
      • Cederblad B.
      • Nordlin K.
      • Alm G.V.
      • Ronnblom L.
      Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus.
      ;
      • Farkas L.
      • Beiske K.
      • Lund-Johansen F.
      • Brandtzaeg P.
      • Jahnsen F.L.
      Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions.
      ;
      • Ronnblom L.
      • Alm G.V.
      An etiopathogenic role for the type I IFN system in SLE.
      ,
      • Ronnblom L.
      • Alm G.V.
      The natural interferon-alpha producing cells in systemic lupus erythematosus.
      ;
      • Baechler E.C.
      • Batliwalla F.M.
      • Karypis G.
      • Gaffney P.M.
      • Ortmann W.A.
      • Espe K.J.
      • et al.
      Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.
      ;
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Like T-cell-derived IFN-γ, also pDC-derived IFN-α is a potent mediator of the expression of CXCR3 ligands. IFN-α induces in a rapid manner CXCL9, CXCL10, and CXCL11 in primary keratinocytes, dermal fibroblasts, and dermal endothelial cells (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Taken together, these observations suggest a central role for pDCs and their secreted product, IFN-α, in the pathogenesis of LE (
      • Blanco P.
      • Palucka A.K.
      • Gill M.
      • Pascual V.
      • Banchereau J.
      Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.
      ;
      • Ronnblom L.
      • Alm G.V.
      A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus.
      ).

      Chemokines in the pathogenesis of lichen planus

      LP represents an autoimmune disease of unknown etiology (
      • Boyd A.S.
      • Neldner K.H.
      Lichen planus.
      ). Clinically, LP is characterized by a subacute or chronically progressive appearance of polygonal papules (
      • Boyd A.S.
      • Neldner K.H.
      Lichen planus.
      ). Histologically, LP shows apoptosis of keratinocytes, acanthosis, hypergranulosis, and alymphocytoid cell-rich infiltrate in upper dermis, leading to the destruction of the basal-cell layer (
      • Sontheimer R.D.
      • Gilliam J.N.
      Immunologically mediated epidermal cell injury.
      ).
      • Fah J.
      • Pavlovic J.
      • Burg G.
      Expression of MxA protein in inflammatory dermatoses.
      demonstrated by immunohistochemical analysis a marked induction of the IFN-α-inducible protein MxA in the upper dermis of lesional LP compared to healthy skin. Very recently, several studies have shown the presence and accumulation of pDC in lesional LP (
      • Santoro A.
      • Majorana A.
      • Roversi L.
      • Gentili F.
      • Marrelli S.
      • Vermi W.
      • et al.
      Recruitment of dendritic cells in oral lichen planus.
      ;
      • de Vries H.J.
      • van Marle J.
      • Teunissen M.B.
      • Picavet D.
      • Zorgdrager F.
      • Bos J.D.
      • et al.
      Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells.
      ;
      • Wenzel J.
      • Scheler M.
      • Proelss J.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated cytotoxic inflammation in lichen planus.
      ). Taken together, these results indicate that pDC were activated in LP and produce large amounts of IFN-α. However, our knowledge of the pathogenetic role of the chemokines in LP is fairly incomplete. Notably, in line with the observation described above, the induction of the IFN-α-inducible CXCR3 ligands CXCL9, CXCL10, and CXCL11 has been reported (
      • Spandau U.
      • Toksoy A.
      • Goebeler M.
      • Brocker E.B.
      • Gillitzer R.
      MIG is a dominant lymphocyte-attractant chemokine in lichen planus lesions.
      ;
      • Flier J.
      • Boorsma D.M.
      • van Beek P.J.
      • Nieboer C.
      • Stoof T.J.
      • Willemze R.
      • et al.
      Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation.
      ;
      • Wenzel J.
      • Scheler M.
      • Proelss J.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated cytotoxic inflammation in lichen planus.
      ). Furthermore, oral LP lesions show marked expression of the inflammatory CXCR3 ligands as well as the presence of homeostatic chemokine CXCL12 (
      • Ichimura M.
      • Hiratsuka K.
      • Ogura N.
      • Utsunomiya T.
      • Sakamaki H.
      • Kondoh T.
      • et al.
      Expression profile of chemokines and chemokine receptors in epithelial cell layers of oral lichen planus.
      ). In oral LP, high levels of CCL20 and its receptor CCR6 were observed, suggesting the recruitment of dendritic cell precursors by interaction of CCL20/CCR6 (
      • Ichimura M.
      • Hiratsuka K.
      • Ogura N.
      • Utsunomiya T.
      • Sakamaki H.
      • Kondoh T.
      • et al.
      Expression profile of chemokines and chemokine receptors in epithelial cell layers of oral lichen planus.
      ).

      Chemokine-driven recruitment of pDC and cytotoxic T cells in LTR: a self-sustaining amplification loop

      During lichenoid skin inflammation a complex cocktail of homeostatic and inflammatory mediators is present. Their temporal and spatial distribution will determine the recruitment of pathogenic leukocyte subsets. In vitro, both the migration of pDCs and of skin-homing memory T cells is regulated by the synergistic action of inflammatory chemokines, such as CXCL9 and CXCL10 and by homeostatic chemokines, such as CXCL12 (
      • Vanbervliet B.
      • Bendriss-Vermare N.
      • Massacrier C.
      • Homey B.
      • de Bouteiller O.
      • Briere F.
      • et al.
      The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12.
      ;
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). In vivo analyses demonstrate that this cooperation of chemokines is mediated by CXCL10-induced priming of lymphocytes (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). Notably, in cutaneous lesions of LE, CXCL12 is coexpressed at similar anatomical locations with the inflammatory CXCR3 ligands CXCL9 and CXCL10 (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ). As mentioned above, oral LP lesions show marked expression of these chemokines (
      • Ichimura M.
      • Hiratsuka K.
      • Ogura N.
      • Utsunomiya T.
      • Sakamaki H.
      • Kondoh T.
      • et al.
      Expression profile of chemokines and chemokine receptors in epithelial cell layers of oral lichen planus.
      ). Hence, a synergistic cooperation of homeostatic and inflammatory chemokines may support the recruitment of pDC and skin-homing memory T cells into sites of autoimmune skin inflammation (
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ,
      • Meller S.
      • Lauerma A.I.
      • Kopp F.M.
      • Winterberg F.
      • Anthoni M.
      • Muller A.
      • et al.
      Chemokine responses distinguish chemical-induced allergic from irritant skin inflammation: memory T cells make the difference.
      ). Within the skin, pDC-derived IFN-α, in concert with T-cell-derived IFN-γ, may increase chemokine production and amplify the recruitment of leukocytes, finally leading to the development of a LTR phenotype.

      Innate activation of plasmacytoid dendritic cells in LTRs

      In LE pDC appear to be activated by circulating immune complexes consisting of autoantibodies and self-nucleic acids (
      • Ronnblom L.
      • Eloranta M.L.
      • Alm G.V.
      Role of natural interferon-alpha producing cells (plasmacytoid dendritic cells) in autoimmunity.
      ). These immune complexes are deposited at the dermo-epidermal junction and activate infiltrating pDC through endosomal TLR7 and 9 following Fcγ-mediated uptake (
      • Farkas L.
      • Beiske K.
      • Lund-Johansen F.
      • Brandtzaeg P.
      • Jahnsen F.L.
      Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions.
      ;
      • Bave U.
      • Magnusson M.
      • Eloranta M.L.
      • Perers A.
      • Alm G.V.
      • Ronnblom L.
      Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG.
      ). In LP the triggers of pDC activation are unknown. The presence of human herpes virus type 7 in LP has been recently linked to the presence of pDC in these lesions (
      • de Vries H.J.
      • van Marle J.
      • Teunissen M.B.
      • Picavet D.
      • Zorgdrager F.
      • Bos J.D.
      • et al.
      Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells.
      ;
      • de Vries H.J.
      • Teunissen M.B.
      • Zorgdrager F.
      • Picavet D.
      • Cornelissen M.
      Lichen planus remission is associated with a decrease of human herpes virus type 7 protein expression in plasmacytoid dendritic cells.
      ). This finding suggests that infection with human herpes virus type 7, a single stranded DNA virus, triggers pDC activation in LP through TLR9. Also virus-specific T cells recruited in response to viral antigens in lesional LP could mediate the cytolytic attack on keratinocytes (
      • De Panfilis G.
      CD8+ cytolytic T lymphocytes and the skin.
      ;
      • Pilli M.
      • Penna A.
      • Zerbini A.
      • Vescovi P.
      • Manfredi M.
      • Negro F.
      • et al.
      Oral lichen planus pathogenesis: a role for the HCV-specific cellular immune response.
      ). The development of LP lesions can be induced by local skin injury, the so-called Koebner phenomenon. Mechanical or chemical injury of the skin with disruption of the epidermal permeability barrier induces the expression of the endogenous antimicrobial peptide LL37 (also known as cathelicidin;
      • Dorschner R.A.
      • Pestonjamasp V.K.
      • Tamakuwala S.
      • Ohtake T.
      • Rudisill J.
      • Nizet V.
      • et al.
      Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus.
      ;
      • Aberg K.M.
      • Man M.Q.
      • Gallo R.L.
      • Ganz T.
      • Crumrine D.
      • Brown B.E.
      • et al.
      Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers.
      ).
      • Lande R.
      • Gregorio J.
      • Facchinetti V.
      • Chatterjee B.
      • Wang Y.H.
      • Homey B.
      • et al.
      Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.
      provided a unique explanation for the Koebner phenomenon in psoriasis by showing that, through this pathway, LL37 induced by skin injury triggers the activation of pDC and the elicitation of autoimmune inflammation in psoriasis. We propose that the Koebner phenomenon may similarly trigger LP. Also, UV injury to the skin may trigger pDC activation and the development of LE through the induction of LL37. This is in accordance to the finding that UV can trigger LL37 expression in keratinocytes (
      • Kim J.E.
      • Kim B.J.
      • Jeong M.S.
      • Seo S.J.
      • Kim M.N.
      • Hong C.K.
      • et al.
      Expression and modulation of LL-37 in normal human keratinocytes, HaCaT cells, and inflammatory skin diseases.
      ). Thus, a common innate immune pathway may trigger different downstream responses and development of different disease entities according to genetic predisposition.

      Conclusion

      We speculate that clinical manifestations of LP and LE are initiated by innate infiltration and -activation of pDC to produce type I IFNs. Activation of skin pDC occurs through deposition of circulating self-nucleic acid containing immune complexes (in LE), through viruses infecting the skin (human herpes virus type 7 in LP), or through mechanical injury to the skin with the formation of LL37/self-DNA complexes (Koebner phenomenon in LP and UV injury in LE). Self-DNA coupled with antimicrobial peptide may induce innate immune responses by activation of pDC leading to the production of IFN-α. On the one hand, IFN-α mediates the activation of IFN-γ secreting cytotoxic T cells either directly or through the bystander maturation of myeloid DC. On the other hand, IFN-α induces the production of CXCR3 ligands in structural cells of the skin, thus promoting the recruitment of more cytotoxic TH1 cells and pDC into the lesion. The TH1 cytokines from cytotoxic T cells further strengthen the production of CXCR3 ligands, finally leading to the development of a LTR phenotype (Figure 1). Taken together, chemokines mediate the initiation and amplification of the pathogenic innate and adaptive immune cascade leading LTR. Therefore, chemokine antagonists may provide new therapeutic approaches in LTR.

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