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Psoriasis Caught in the NET

      A report in the June 2019 issue of the Journal of Investigative Dermatology reveals a role of neutrophil extracellular traps (NETs) in the induction of T helper type 17 cell responses and shows the relevance of this pathway in patients with psoriasis carrying a common risk variant in the TRAF3IP2 gene (Lambert et al., 2019). This work provides a new piece to the puzzle that links neutrophils to the T helper type 17–mediated pathogenesis of psoriasis.
      • NETs released by neutrophils induce T helper type 17 responses in psoriasis
      • The TRAF3IP2 gene risk variant unravels the pathogenic role of the NET-T helper type 17 pathway and provides evidence of a genetic basis for the increased IL-17 expression in psoriasis
      • NETs may represent upstream drug targets for the treatment of psoriasis

      Introduction

      Over the past decade, tremendous advances in understanding the pathogenesis of psoriasis have been made. The discovery of the T helper type 17 (Th17) subset of CD4+ T cells producing IL-17 in 2004 has led to the identification of the central role of Th17 cells in the pathogenesis of psoriasis. These discoveries were initially made in the context of expression studies, showing high levels of IL-17A in skin lesions of plaque psoriasis (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Aphale A.
      • Vatan L.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ,
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ), and later confirmed by the efficacy of treatments targeting IL-17A (
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • Reich K.
      • Griffiths C.E.
      • Papp K.
      • et al.
      Secukinumab in plaque psoriasis--results of two phase 3 trials.
      ) or its receptor (
      • Papp K.A.
      • Leonardi C.
      • Menter A.
      • Ortonne J.P.
      • Krueger J.G.
      • Kricorian G.
      • et al.
      Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.
      ). These findings, along with the recent identification of psoriatic T-cell autoantigens (
      • Arakawa A.
      • Siewert K.
      • Stöhr J.
      • Besgen P.
      • Kim S.M.
      • Rühl G.
      • et al.
      Melanocyte antigen triggers autoimmunity in human psoriasis.
      ,
      • Lande R.
      • Botti E.
      • Jandus C.
      • Dojcinovic D.
      • Fanelli G.
      • Conrad C.
      • et al.
      The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.
      ), have positioned plaque psoriasis as a Th17-mediated autoimmune disease.
      Neutrophils, the most abundant leukocytes in humans, are present in lesions of plaque psoriasis, but whether or not they play a role in pathogenesis is unclear. During formation of psoriatic plaques, neutrophils infiltrate the dermis (
      • Albanesi C.
      • Scarponi C.
      • Pallotta S.
      • Daniele R.
      • Bosisio D.
      • Madonna S.
      • et al.
      Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment.
      ) and subsequently migrate into the epidermis and the stratum corneum to form spongiform pustules of Kogoj and Munro’s microabscesses. Hints for a pathogenic role of neutrophils in plaque psoriasis come from the clinical observation that drug-induced agranulocytosis can improve psoriasis, whereas normalization of neutrophil counts is associated with disease exacerbation (
      • Toichi E.
      • Tachibana T.
      • Furukawa F.
      Rapid improvement of psoriasis vulgaris during drug-induced agranulocytosis.
      ). Furthermore, in mouse models, inhibition of microabscess formation blocks psoriasis development (
      • Karbach S.
      • Croxford A.L.
      • Oelze M.
      • Schüler R.
      • Minwegen D.
      • Wegner J.
      • et al.
      Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.
      ). Neutrophils infiltrating psoriatic plaques are activated and undergo a specialized form of cell death termed NETosis, which is associated with the release of neutrophil extracellular traps (NETs;
      • Lin A.M.
      • Rubin C.J.
      • Khandpur R.
      • Wang J.Y.
      • Riblett M.
      • Yalavarthi S.
      • et al.
      Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.
      ,
      • Hu S.C.
      • Yu H.S.
      • Yen F.L.
      • Lin C.L.
      • Chen G.S.
      • Lan C.C.
      Neutrophil extracellular trap formation is increased in psoriasis and induces human beta-defensin-2 production in epidermal keratinocytes.
      ). NETs are web-like antimicrobial structures that consist of decondensed DNA associated with granular proteins, including antimicrobial peptides and proteases (
      • Brinkmann V.
      • Reichard U.
      • Goosmann C.
      • Fauler B.
      • Uhlemann Y.
      • Weiss D.S.
      • et al.
      Neutrophil extracellular traps kill bacteria.
      ). NETs have been associated with autoimmunity in small vessel vasculitis (
      • Kessenbrock K.
      • Krumbholz M.
      • Schönermarck U.
      • Back W.
      • Gross W.L.
      • Werb Z.
      • et al.
      Netting neutrophils in autoimmune small-vessel vasculitis.
      ), lupus (
      • Villanueva E.
      • Yalavarthi S.
      • Berthier C.C.
      • Hodgin J.B.
      • Khandpur R.
      • Lin A.M.
      • et al.
      Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.
      ,
      • Guiducci C.
      • Tripodo C.
      • Gong M.
      • Sangaletti S.
      • Colombo M.P.
      • Coffman R.L.
      • et al.
      Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9.
      ,
      • Lande R.
      • Ganguly D.
      • Facchinetti V.
      • Frasca L.
      • Conrad C.
      • Gregorio J.
      • et al.
      Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus.
      ), and rheumatoid arthritis (
      • Demoruelle M.K.
      • Harrall K.K.
      • Ho L.
      • Purmalek M.M.
      • Seto N.L.
      • Rothfuss H.M.
      • et al.
      Anti-citrullinated protein antibodies are associated with neutrophil extracellular traps in the sputum in relatives of rheumatoid arthritis patients.
      ); however, whether or not they play a role in Th17-mediated autoimmunity in psoriasis was not known.

      The NET-Th17 axis in psoriasis

      In this study,
      • Lambert S.
      • Hambro C.A.
      • Johnston A.
      • Stuart P.E.
      • Tsoi L.C.
      • Nair R.P.
      • Elder J.T.
      Neutrophil extracellular traps induce human Th17 cells: effect of psoriasis-associated TRAF3IP2 genotype.
      identify a link between NETs and Th17 responses in psoriasis. First, they show that NETs released by activated neutrophils can induce memory CD4 T cells to acquire a Th17 cell phenotype in the context of polyclonal anti-CD3/anti-CD28 stimulation of healthy peripheral blood mononuclear cells. These memory T cells secrete IL-17A and express IL-17F and RORC, but not Th17 cytokines, suggesting a specificity of NETs for Th17 induction. Second, they find that NET-mediated Th17 induction is increased in psoriasis patients carrying a risk variant in the TRAF3IP2 gene. The TRAF3IP2 gene encodes Act1, an adaptor molecule that negatively regulates signal transducer and activator of transcription 3 (STAT3) activation in Th17 cells (
      • Zhang C.J.
      • Wang C.
      • Jiang M.
      • Gu C.
      • Xiao J.
      • Chen X.
      • et al.
      Act1 is a negative regulator in T and B cells via direct inhibition of STAT3.
      ). The psoriatic variant Act1 D10N promotes unrepressed signal transducer and activator of transcription 3 activation of Th17 cells, leading to enhanced IL-17 production in psoriasis patients. These findings provide unique insights into the role of the NET-Th17 axis in psoriasis and suggest a genetic basis for the increased IL-17 levels in psoriasis. However, how do NETs induce Th17 cells?
      • Lambert S.
      • Hambro C.A.
      • Johnston A.
      • Stuart P.E.
      • Tsoi L.C.
      • Nair R.P.
      • Elder J.T.
      Neutrophil extracellular traps induce human Th17 cells: effect of psoriasis-associated TRAF3IP2 genotype.
      show that, in the context of polyclonal peripheral blood mononuclear cells stimulation, NETs induce Th17 cells via monocytes that interact with T cells in a contact-dependent manner. Most likely, NETs activate monocytes to secrete Th17 polarizing cytokines and, at the same time, to express costimulatory molecules that engage with Th17 cells. In fact, NETs contain the antimicrobial peptide LL37 that triggers activation of monocytes and other antigen-presenting cells through the formation of complexes with NET-DNA. NET-derived LL37–DNA complexes are resistant to nuclease degradation and have the unique ability to access intracellular compartments, where they trigger activation of endosomal toll-like receptor 9 (
      • 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.
      ,
      • Lande R.
      • Ganguly D.
      • Facchinetti V.
      • Frasca L.
      • Conrad C.
      • Gregorio J.
      • et al.
      Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus.
      ) and cytosolic cGAS/STING (
      • Lood C.
      • Blanco L.P.
      • Purmalek M.M.
      • Carmona-Rivera C.
      • De Ravin S.S.
      • Smith C.K.
      • et al.
      Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.
      ,
      • Chamilos G.
      • Gregorio J.
      • Meller S.
      • Lande R.
      • Kontoyiannis D.P.
      • Modlin R.L.
      • et al.
      Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37.
      ). In response to NET-derived LL37–DNA complexes, monocytes produce pro-inflammatory cytokines, including IL-6, tumor necrosis factor, and IL-12/23. In addition, NET-derived LL37 alone can activate the P2X7 receptor on monocytes, leading to inflammasome activation and secretion of IL-1β (
      • Kahlenberg J.M.
      • Carmona-Rivera C.
      • Smith C.K.
      • Kaplan M.J.
      Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages.
      ). These findings appear to be relevant as IL-1β, IL-6, and IL-23 act synergistically to drive Th17 cell responses (
      • Volpe E.
      • Servant N.
      • Zollinger R.
      • Bogiatzi S.I.
      • Hupé P.
      • Barillot E.
      • et al.
      A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.
      ). LL37-DNA complexes also induce maturation of monocytes, although it is not known whether or not they stimulate a specific costimulatory molecule profile, such as ICOSL and OX40L, that preferentially induces Th17 cells (
      • Xin L.
      • Jiang T.T.
      • Chaturvedi V.
      • Kinder J.M.
      • Ertelt J.M.
      • Rowe J.H.
      • et al.
      Commensal microbes drive intestinal inflammation by IL-17-producing CD4+ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2.
      ).
      Finally,
      • Lambert S.
      • Hambro C.A.
      • Johnston A.
      • Stuart P.E.
      • Tsoi L.C.
      • Nair R.P.
      • Elder J.T.
      Neutrophil extracellular traps induce human Th17 cells: effect of psoriasis-associated TRAF3IP2 genotype.
      show that NET-induced Th17 cells arise from memory and not naïve T cells present in peripheral blood mononuclear cells, suggesting that NETs expand precommitted memory Th17 cells. This finding is relevant for psoriasis as the pathogenic Th17 cells reside in the skin as tissue memory cells and not naïve T cells (
      • Cheuk S.
      • Schlums H.
      • Gallais Sérézal I.
      • Martini E.
      • Chiang S.C.
      • Marquardt N.
      • et al.
      CD49a expression defines tissue-resident CD8(+) T cells poised for cytotoxic function in human skin.
      ). However, NET-induced reprogramming of memory T cells into Th17 cells should also be considered, especially in the light of the recent finding that committed memory Th cells contain a subpopulation of cells with functional plasticity (
      • Karmaus P.W.F.
      • Chen X.
      • Lim S.A.
      • Herrada A.A.
      • Nguyen T.M.
      • Xu B.
      • et al.
      Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity.
      ).

      NET-driven autoimmunity in psoriasis

      In addition to their role in innate immune activation, NETs represent major autoantigenic targets for autoantibody and immune complex formation in rheumatologic disorders (
      • Grayson P.C.
      • Kaplan M.J.
      At the Bench: neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases.
      ). NET-associated MPO and Proteinase 3 are autoantigens in autoimmune small vessel vasculitis (
      • Kessenbrock K.
      • Krumbholz M.
      • Schönermarck U.
      • Back W.
      • Gross W.L.
      • Werb Z.
      • et al.
      Netting neutrophils in autoimmune small-vessel vasculitis.
      ), NET-derived LL37 and HNP represent autoantigens in lupus (
      • Lande R.
      • Ganguly D.
      • Facchinetti V.
      • Frasca L.
      • Conrad C.
      • Gregorio J.
      • et al.
      Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus.
      ), and NET-derived vimentin and histones are autoantigens in rheumatoid arthritis (
      • Corsiero E.
      • Bombardieri M.
      • Carlotti E.
      • Pratesi F.
      • Robinson W.
      • Migliorini P.
      • et al.
      Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs.
      ). The ability of NETs to break tolerance to NET-associated autoantigens appears to be related to their ability to induce type I IFN production by plasmacytoid dendritic cells via LL37-DNA complexes (
      • Lande R.
      • Ganguly D.
      • Facchinetti V.
      • Frasca L.
      • Conrad C.
      • Gregorio J.
      • et al.
      Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus.
      ). However, what about the role of NETs in psoriasis autoimmunity? In psoriasis, LL37-DNA complexes trigger type I IFN production by plasmacytoid dendritic cells (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.
      ,
      • 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.
      ,
      • Ganguly D.
      • Chamilos G.
      • Lande R.
      • Gregorio J.
      • Meller S.
      • Facchinetti V.
      • et al.
      Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.
      ) and LL37 was shown to represent a T-cell autoantigen recognized by T cells (
      • Lande R.
      • Botti E.
      • Jandus C.
      • Dojcinovic D.
      • Fanelli G.
      • Conrad C.
      • et al.
      The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.
      ). LL37-specific T cells may be pathogenic in psoriasis as they are present skin lesions, produce IL-17A, and their blood frequency correlates with disease severity (
      • Lande R.
      • Botti E.
      • Jandus C.
      • Dojcinovic D.
      • Fanelli G.
      • Conrad C.
      • et al.
      The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.
      ). NET-derived LL37 may induce potent innate activation of monocytes that drive Th17 skewing, and mature into professional antigen-presenting cells that present LL37 to specific autoimmune T cells. Activated LL37 specific Th17 cells may then migrate into the epidermis and recognize LL37 peptides expressed by keratinocytes in the context of major histocompatibility complex molecules (Figure 1). This could lead to production of IL-17 and other Th17 cytokines, which sustain LL37 expression by keratinocytes and trigger the expression of neutrophil-recruiting chemokines, such as CXCL1/2 and IL-8 (Figure 1).
      Figure thumbnail gr1
      Figure 1NETs promote Th17 cell activation and autoimmunity in psoriasis. Psoriatic NETs consist of DNA strands decorated with antimicrobial peptides such as LL37. NET-derived LL37–DNA complexes directly activate endosomal toll-like receptor 9 or cytosolic STING in monocytes and other antigen-presenting cells. This leads to the induction of pro-inflammatory Th17-polarizing cytokines, such as IL-6, tumor necrosis factor, and IL-23. LL37 alone also stimulates inflammasome activation in monocytes through the activation of P2X7 receptors, leading to the production of IL-1β. Furthermore, activation of monocytes and antigen-presenting cells leads to cell maturation with upregulation of Th17 cell polarizing costimulatory molecules and LL37 antigen presentation in the context of major histocompatibility complex class I and II molecules. This leads, on the one hand, to Th17 skewing of skin-resident memory Th17 cells and, on the other hand, to activation of LL37-specific T cells. Th17 induction occurs via cytokine-induced STAT3 activation. This process is amplified in psoriasis patients carrying the TRAF3IP2 gene that codes for Act1, a repressor of the activation of STAT3. LL37-specific Th17 cells migrate into the epidermis, where they recognize LL37 and produce large amounts of IL-17A. Th17-derived cytokines also induce the production of neutrophil-recruiting chemokines by keratinocytes, thereby sustaining the inflammatory process. NET, neutrophil extracellular trap; STAT3, signal transducer and activator of transcription 3; Th17, T helper type 17.

      Summary and open questions

      This study provides key elements implicating NETs in the pathogenesis of plaque psoriasis. The study found that NETs specifically induce Th17 cell responses and shows that this pathway is relevant in psoriatic patients carrying a common risk variant. However, why does NET-induced Th17 cell autoimmunity only occur in plaque psoriasis and not in pustular forms of psoriasis, which are characterized by much larger collections of neutrophils? Pustular psoriasis appears to be stuck in a neutrophil-driven autoinflammatory loop in which proteases proteinase 3, elastase, and cathepsin G contained in NETs cleave IL-36 into a truncated, biologically more active form (
      • Henry C.M.
      • Sullivan G.P.
      • Clancy D.M.
      • Afonina I.S.
      • Kulms D.
      • Martin S.J.
      Neutrophil-derived proteases escalate inflammation through activation of IL-36 family cytokines.
      ). Cleaved IL-36 then further recruits netting neutrophils through activation of keratinocytes producing CXCL1/2 and CXCL8, leading to a self-sustaining IL-36-neutrophil loop (
      • Liang Y.
      • Sarkar M.K.
      • Tsoi L.C.
      • Gudjonsson J.E.
      Psoriasis: a mixed autoimmune and autoinflammatory disease.
      ). The central role of IL-36 was recently confirmed by a clinical study in seven patients, showing improvement of pustular psoriasis in patients treated with an anti-IL-36 antibody (
      • Bachelez H.
      • Choon S.E.
      • Marrakchi S.
      • Burden A.D.
      • Tsai T.F.
      • Morita A.
      • et al.
      Inhibition of the Interleukin-36 pathway for the treatment of generalized pustular psoriasis.
      ). Furthermore, pustular psoriasis was associated with loss-of-function mutations in the IL-36R antagonist, which are known to drive increased IL-36 signaling (
      • Marrakchi S.
      • Guigue P.
      • Renshaw B.R.
      • Puel A.
      • Pei X.Y.
      • Fraitag S.
      • et al.
      Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
      ,
      • Onoufriadis A.
      • Simpson M.A.
      • Pink A.E.
      • Di Meglio P.
      • Smith C.H.
      • Pullabhatla V.
      • et al.
      Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
      ) and mutations in the AP1S3 and CARD14 genes, affecting NfkB signaling in keratinocytes and increasing expression of IL-36 (
      • Setta-Kaffetzi N.
      • Simpson M.A.
      • Navarini A.A.
      • Patel V.M.
      • Lu H.C.
      • Allen M.H.
      • et al.
      AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ). Pustular psoriasis appears to lack gene variants that promote Th17 induction and T-cell autoimmunity in response to NETs. The NET-based culture system described by
      • Lambert S.
      • Hambro C.A.
      • Johnston A.
      • Stuart P.E.
      • Tsoi L.C.
      • Nair R.P.
      • Elder J.T.
      Neutrophil extracellular traps induce human Th17 cells: effect of psoriasis-associated TRAF3IP2 genotype.
      will allow investigation of the roles of other identified susceptibility genes in Th17 cell induction (e.g., IL.23A, IL.23R variants), as well as induction of autoimmunity (e.g., type I IFN-signaling related gene variants, such as IFIH1 and Tyk2, and antigen-presentation variants, such as ERAP1/2 and Cw0602).
      Another key question is how NETs are activated in psoriasis. Given the essential antimicrobial function of NETs and the fact that NETs are typically induced by bacterial products, it is tempting to speculate that a dysbiotic microbiota in psoriatic skin drives the sustained NETosis and Th17 polarization in psoriatic skin (
      • Chang H.W.
      • Yan D.
      • Singh R.
      • Liu J.
      • Lu X.
      • Ucmak D.
      • et al.
      Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization.
      ). On the other hand, it is also clear that, in the context of non-infectious inflammation, NETs can be induced by inflammatory mediators, such as IL-8 or type I IFNs (
      • Brinkmann V.
      • Reichard U.
      • Goosmann C.
      • Fauler B.
      • Uhlemann Y.
      • Weiss D.S.
      • et al.
      Neutrophil extracellular traps kill bacteria.
      ,
      • Martinelli S.
      • Urosevic M.
      • Daryadel A.
      • Oberholzer P.A.
      • Baumann C.
      • Fey M.F.
      • et al.
      Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation.
      ). Intriguingly, a new study shows that in patients with severe psoriasis, NETs are released by circulating low-density granulocytes (
      • Teague H.L.
      • Varghese N.J.
      • Tsoi L.C.
      • Dey A.K.
      • Garshick M.S.
      • Silverman J.I.
      • et al.
      Neutrophil subsets, platelets, and vascular disease in psoriasis.
      ), and they correlate with disease activity and development of cardiovascular comorbidities in psoriasis. The correlation between increased number of NETotic cells and disease activity has been previously reported (
      • Hu S.C.
      • Yu H.S.
      • Yen F.L.
      • Lin C.L.
      • Chen G.S.
      • Lan C.C.
      Neutrophil extracellular trap formation is increased in psoriasis and induces human beta-defensin-2 production in epidermal keratinocytes.
      ), suggesting a role of netting neutrophils beyond the skin, at least in the case of wide-spread psoriasis. NETosis appears to be induced by platelet adherence to low-density granulocytes, although the relevance of such stimulus in the pathogenesis of psoriasis is unclear.

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      Linked Article

      • Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype
        Journal of Investigative DermatologyVol. 139Issue 6
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          Psoriasis lesions are rich in IL-17–producing T cells as well as neutrophils, which release webs of DNA-protein complexes known as neutrophil extracellular traps (NETs). Because we and others have observed increased NETosis in psoriatic lesions, we hypothesized that NETs contribute to increased T helper type 17 (Th17) cells in psoriasis. After stimulating peripheral blood mononuclear cells with anti-CD3/CD28 beads for 7 days, we found significantly higher percentages of CD3+CD4+IL-17+ (Th17) cells in the presence versus absence of NETs, as assessed by flow cytometry, IL-17 ELISA, and IL17A/F and RORC mRNAs.
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