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Defining Upstream Elements of Psoriasis Pathogenesis: An Emerging Role For Interferon α

2005; Elsevier BV; Volume: 125; Issue: 5 Linguagem: Inglês

10.1111/j.0022-202x.2005.23923.x

1523-1747

Frank O. Nestlé, Michel Gilliet,

T-cell and B-cell Immunology

Psoriasis is a common chronic-relapsing immune-mediated pathology involving skin and joints of genetically predisposed individuals (Nickoloff and Nestle, 2004Nickoloff B.J. Nestle F.O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.J Clin Invest. 2004; 113: 1664-1675Crossref PubMed Scopus (466) Google Scholar; Schon and Boehncke, 2005Schon M.P. Boehncke W.H. Psoriasis.N Engl J Med. 2005; 352: 1899-1912Crossref PubMed Scopus (1006) Google Scholar), which potentially shares disease pathways with other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease (Davidson and Diamond, 2001Davidson A. Diamond B. Autoimmune diseases.N Engl J Med. 2001; 345: 340-350Crossref PubMed Scopus (867) Google Scholar). The pathogenesis of psoriasis is dependent on activation and expansion of lesional and/or circulating T cells culminating in a psoriasiform angiogenic tissue reaction and epidermal hyperplasia (Boyman et al., 2004Boyman O. Hefti H.P. Conrad C. Nickoloff B.J. Suter M. Nestle F.O. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T Cells and tumor necrosis factor-{alpha}.J Exp Med. 2004; 199: 731-736Crossref PubMed Scopus (411) Google Scholar). Based on the analysis of infiltrating cell types, their secreted products, and genetic signatures present in lesional skin, psoriasis is regarded as a type-1 tissue reaction with a prominent role for T cell-derived interferon (IFN)-γ (Nestle et al., 1994Nestle F.O. Turka L.A. Nickoloff B.J. Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.J Clin Invest. 1994; 94: 202-209Crossref PubMed Google Scholar; Lew et al., 2004Lew W. Bowcock A.M. Krueger J.G. Psoriasis vulgaris: Cutaneous lymphoid tissue supports T-cell activation and "Type 1" inflammatory gene expression.Trends Immunol. 2004; 25: 295-305Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). Given that environmental factors such as mechanical stress and infections of the skin represent a common trigger for disease relapses, much effort has been devoted to understanding the link between these unspecific stimuli and the pathogenic T cell cascade leading to psoriasis. Recent evidence suggests that type-1 IFN, a class of cytokines produced at early stages of the innate immune response to pathogens, may represent the missing link. Type I IFN contain various family members (IFN-α subtypes, -β, -ε, -κ, -ω, -δ, -τ), the most abundant and best-studied being IFN-α and -β. Although IFN-α/β can be produced by virtually all cells of the human organism, plasmacytoid dendritic cells (PDC), or "natural IFN-producing cells" (NIPC) have the unique ability to produce up to 1000-fold more IFN-α/β than any other cell type (Liu et al., 2001Liu Y.J. Kanzler H. Soumelis V. Gilliet M. Dendritic cell lineage, plasticity and cross-regulation.Nat Immunol. 2001; 2: 585-589Crossref PubMed Scopus (532) Google Scholar). IFN-α/β share a heterodimeric receptor composed of IFNAR1 and IFNAR2. Ligand binding leads to receptor dimerization, auto-phosphorylation of Janus kinases (JAK), recruitment and phosphorylation of signal transducer and activator of transcription (STAT-1, STAT-2, STAT-3, STAT-4 in some cell types), translocation of STAT homo- and heterodimers into the nucleus, and induced expression of a large numbers of IFN-stimulated genes (ISG), including IFN regulatory factor (IRF)-7, protein kinase (PKR) and myxovirus-resistance (Mx) protein (Theofilopoulos et al., 2005Theofilopoulos A.N. Baccala R. Beutler B. Kono D.H. Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-335Crossref PubMed Scopus (1011) Google Scholar). IRF-7 is of special importance since it has been recently shown to be the master regulator of the IFN-α/β mediated immune response (Honda et al., 2005Honda K. Yanai H. Negishi H. et al.IRF-7 is the master regulator of type-I interferon-dependent immune responses.Nature. 2005; 434: 772-777Crossref PubMed Scopus (1730) Google Scholar). Through the induction of ISG, IFN-α/β exhibits a unique pleiotropy of biological effects primarily aimed at a cellular state of antiviral defense, encompassing growth inhibition and immunomodulation (Theofilopoulos et al., 2005Theofilopoulos A.N. Baccala R. Beutler B. Kono D.H. Type I interferons (alpha/beta) in immunity and autoimmunity.Annu Rev Immunol. 2005; 23: 307-335Crossref PubMed Scopus (1011) Google Scholar). Immunomodulatory effects include upregulation of MHC class I, NK cell activation, and most importantly activation of myeloid dendritic cells. Although never convincingly demonstrated, a potential involvement of IFN-α/β in the pathogenesis of psoriasis has been previously suggested by the following observations: (i) the induction of psoriasis after injection of recombinant IFN-α (Funk et al., 1991Funk J. Langeland T. Schrumpf E. Hanssen L.E. Psoriasis induced by interferon-alpha.Br J Dermatol. 1991; 125: 463-465Crossref PubMed Scopus (149) Google Scholar), (ii) the presence of an activated IFN-α/β signaling pathway in keratinocytes (van der Fits et al., 2004van der Fits L. van der Wel L.I. Laman J.D. Prens E.P. Verschuren M.C. In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered.J Invest Dermatol. 2004; 122: 51-60Crossref PubMed Scopus (101) Google Scholar), and (iii) the development of psoriasiform inflammation in IRF-2 knockout mice (Hida et al., 2000Hida S. Ogasawara K. Sato K. et al.CD8(+) T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling.Immunity. 2000; 13: 643-655Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). A functional role of IFN-α/β in the initiation of psoriasis has been demonstrated very recently (Nestle et al., 2005Nestle F.O. Conrad C. Tun-Kyi A. et al.Plasmacytoid pre-dendritic cells (PDC) initiate psoriasis through IFN-alpha production.J Exp Med. 2005; 202: 135-143Crossref PubMed Scopus (872) Google Scholar). This study showed that IFN-α was not elevated in fully established psoriatic plaques but was transiently produced at very early stages of psoriasis development (Boyman et al., 2004Boyman O. Hefti H.P. Conrad C. Nickoloff B.J. Suter M. Nestle F.O. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T Cells and tumor necrosis factor-{alpha}.J Exp Med. 2004; 199: 731-736Crossref PubMed Scopus (411) Google Scholar) and represented a key innate event leading to the expansion of pathogenic T cells and to their activation into effectors mediating the development of the psoriatic lesion (Nestle et al., 2005Nestle F.O. Conrad C. Tun-Kyi A. et al.Plasmacytoid pre-dendritic cells (PDC) initiate psoriasis through IFN-alpha production.J Exp Med. 2005; 202: 135-143Crossref PubMed Scopus (872) Google Scholar). In this issue, Wessel Eriksen et al provide a link between IFN-α produced during psoriasis development and the T cell effector functions in psoriasis. IFN-α-induced signaling was shown to be increased and prolonged in psoriatic T cells at the level of STAT activation. Increased IFN-α signaling led to increased STAT binding, IFN-γ production, and inhibition of T cell growth. Interestingly, in addition to an increased STAT-1 and STAT-2 activation, Wessel Eriksen et al (2005) also show enhanced STAT-3 activation in psoriatic T cells which complements recent data on the role of activated STAT-3 in psoriatic keratinocytes (Sano et al., 2005Sano S. Chan K.S. Carbajal S. et al.Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model.Nat Med. 2005; 11: 43-49Crossref PubMed Scopus (595) Google Scholar). Wessel Eriksen et al further demonstrate increased STAT-4 activation linking IFN-α sensitivity of psoriatic T cells and generation of lesional Th-1 responses (Kaplan et al., 1996Kaplan M.H. Sun Y.L. Hoey T. Grusby M.J. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.Nature. 1996; 382: 174-177Crossref PubMed Scopus (1055) Google Scholar). The response to IFN-α was specific since STAT responses to other cytokines were not altered. How can we integrate the findings of Wessel Eriksen et al in the current view of the pathogenesis of psoriasis? An integrated view is depicted in Figure 1. In uninvolved skin of psoriatic patients there is an increased number of PDC (Nestle et al., 2005Nestle F.O. Conrad C. Tun-Kyi A. et al.Plasmacytoid pre-dendritic cells (PDC) initiate psoriasis through IFN-alpha production.J Exp Med. 2005; 202: 135-143Crossref PubMed Scopus (872) Google Scholar). Innate activation of PDC to produce IFN-α drives "quiescent" resident T cells in uninvolved psoriatic skin into activated pathogenic effectors. This may occur indirectly through the induction of myeloid DC activation/maturation as suggested for SLE (Blanco et al., 2001Blanco P. Palucka A.K. Gill M. Pascual V. Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.Science. 2001; 294: 1540-1543Crossref PubMed Scopus (1096) Google Scholar). In line with this scenario, myeloid dermal DC in psoriatic skin are activated and have the ability to stimulate autoreactive Th-1 cells (Nestle et al., 1994Nestle F.O. Turka L.A. Nickoloff B.J. Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.J Clin Invest. 1994; 94: 202-209Crossref PubMed Google Scholar). Additional indirect effects of IFN-α on T cells include (i) the enhanced survival and expansion of T cells through induction of IL-15 (Zhang et al., 1998Zhang X. Sun S. Hwang I. Tough D.F. Sprent J. Potent and selective stimulation of memory-phenotype CD8+T cells in vivo by IL-15.Immunity. 1998; 8: 591-599Abstract Full Text Full Text PDF PubMed Scopus (1058) Google Scholar) and (ii) an increased cross-presentation of tissue specific (auto-) antigens by lesional DC (Le Bon et al., 2003Le Bon A. Etchart N. Rossmann C. et al.Cross-priming of CD8+T cells stimulated by virus-induced type I interferon.Nat Immunol. 2003; 4: 1009-1015Crossref PubMed Scopus (671) Google Scholar). Wessel Eriksen et al suggest that IFN-α may also act directly through activation of IFN-α sensitive lesional T cells. Furthermore, increased STAT-4 activation in psoriatic T cells links IFN-α sensitivity and generation of lesional Th-1 responses. These findings further strengthen the emerging concept that IFN-α is an early innate master cytokine in autoimmune diseases including psoriasis and raise several important questions. What causes the increased IFN-α-sensitivity in psoriatic T cells? Is there a genetic component related to increased IFN-α sensitivity? Is the primary defect in psoriasis rather an aberrant activation of the IFN-α pathway as a consequence of the recruitment and the activation of PDC in psoriatic skin? The molecular definition of ligands activating lesional PDC as well as factors involved in the generation and differentiation of lesional pathogenic T cells may provide important clues to answer these questions. How does IFN-α compare to TNF-α, a validated target for psoriasis (Chaudhari et al., 2001Chaudhari U. Romano P. Mulcahy L.D. Dooley L.T. Baker D.G. Gottlieb A.B. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomised trial.Lancet. 2001; 357: 1842-1847Abstract Full Text Full Text PDF PubMed Scopus (881) Google Scholar; Boyman et al., 2004Boyman O. Hefti H.P. Conrad C. Nickoloff B.J. Suter M. Nestle F.O. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T Cells and tumor necrosis factor-{alpha}.J Exp Med. 2004; 199: 731-736Crossref PubMed Scopus (411) Google Scholar)? In contrast to TNF-α, IFN-α production in psoriasis is a transient event occurring early during the psoriatic disease process and is mainly confined to one cell type, dermal PDC. It will be therefore of particular interest to test inhibitors of IFN-α and its signaling pathways as prophylactic and therapeutic agents in psoriasis. Thus, we suggest a spatial and temporal view of psoriasis development, in which PDC-derived IFN-α represents an early and tightly regulated upstream event preceding Th-1 mediated autoimmune inflammation, induced by IFN-α sensitive autoreactive T cells.