An Autocrine Circuit of IL-33 in Keratinocytes Is Involved in the Progression of Psoriasis

IL-33 is constitutively expressed in the skin. Psoriasis a common skin inflammatory disease. The roles of psoriasis have not been well-elucidated. We identified that keratinocytes (KCs) are predominant cells expressing and its receptor, suppression tumorigenicity 2, KCs actively released on stimuli induced psoriasis-related cytokine, chemokine, molecules genes transcription an autocrine manner. IL-33?specific deficiency ameliorated imiquimod-induced psoriatic dermatitis. In addition, intradermal injection recombinant alone psoriasis-like dermatitis, which attributed to transcriptional upregulation enriched IL-17, TNF, chemokine signaling pathway stimulation. Our data demonstrate circuit promotes progression inflammation, potential therapeutic target for psoriasis. results from dysfunction immune (Lowes et al., 2014Lowes M.A. Suárez-Fariñas M. Krueger J.G. 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Antimicrobial peptides psoriasis.J Dermatol. 2012; 39: 225-230Crossref (138) However, IL-17 receptor A or IL-23 deletion do acquire resistance imiquimod (IMQ)-induced dermatitis mice but only partially attenuate disease severity (El Malki 2013El K. Karbach S.H. Huppert Zayoud Reissig Schüler R. al.An alternative inflammation absence interleukin-17 signaling.J Invest 2013; 133: 441-451Abstract (121) van der Fits 2009van L. Mourits Voerman J.S. Kant Boon Laman J.D. al.Imiquimod-induced mediated via IL-23/IL-17 axis.J 2009; 182: 5836-5845Crossref (985) Besides, every patient with can completely recover after application IL-23? IL-17A?targeting antibodies Scholar), implying involvement cytokines IL-33, member IL-1 family, plays important role tissue homeostasis. functions cytokine binding 2 (ST2) (Schmitz 2005Schmitz Owyang A. Oldham E. Song Y. 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KCs-specific injection?induced mice. vitro, stimulation downstream study suggests involved may be To clarify skin-derived psoriasis, samples without collected detection. demographics these shown Supplementary Table S1. Western blot showed compared normal (Figure 1a). Analyzing four Gene Omnibus datasets elevated paired nonlesional 1b). about 1.65-fold 1c). significantly raised those 1d e). Figure S1 illustrates induction After smearing IMQ 5 consecutive days, treated obvious phenotype pathological features. These suggest containing pretherapy posttherapy before TNF inhibitor, higher than skin, whereas it decreased inhibition 12 weeks 1f). Likewise, tendency decrease treatment anti–IL-17 antibody 43 days Further analysis suggested positively related IL-17A 1g). indicate associated assess Il-33?/? St2?/? subjected Compared wild-type (WT) mice, phenotypes, including erythema, scaling, thickening, relieved 2a). scores 2b), vascular hyperplasia, manifesting thinner blood vessels fewer branches 2c), reduced thicknesses epidermis dermis numbers Munro’s microabscess (black arrow) vessel (red 2d Not back ear all features greatly attenuated 2f g). manifestations markedly (Supplementary S2). confirm subcutaneously injected at 1 day application, times total S3a). obviously S3b–e). Together, IL-33/ST2 critical uncover impacts single-cell suspensions prepared spleen, lymph nodes analyzed flow cytometry. gating strategy S4. frequency absolute number (CD45+), mildly percentage (CD45+Ly6G+), grossly mast (CD45+CD11c+) (CD45+F4/80+), did affect their 3a). For knockout (CD3+), Th (CD3+CD4+), (CD3+CD4+17A+). Dermal ?? TCR low producer (Cai 2011Cai Shen X. Ding al.Pivotal dermal IL-17-producing [published correction appears Immunity 2011;35:649].Immunity. 2011; 35: 596-610Abstract (635) CD3+?? TCRlow IL-17A+ Among CD3+CD4+ few IFN-? positive three groups 3b). spleen nodes, two pathogenic show any significant difference St2?/– WT 3c d). affecting rather peripheral organs, skin?derived IL-33. generated cross transplantation dorsal 4a). recipient donor score 4b) 4c Similar changes observed Notably, histological similar 4b–d). verify determine relationship mouse intradermally ears Il-17A?/? 10 S5a), S5b). H&E staining typical acanthosis, parakeratosis, formation S5c). All no S5b c). CD45+ macrophages, especially above S5d Taken together, IL-33?alone necessary process, suggesting inflammation. major immunohistochemistry immunofluorescence staining. IL-33–positive (brown) found mainly almost present distributed predominantly slightly 4e f). Immunofluorescence signal staining) colocalized K14–positive (green epidermis, indicating accumulated nuclei 4g). Collectively, toward KC?derived address whether KC-derived regulates K5-Cre transgenic crossed floxed selectively ablate KCs. Immunohistochemistry there epidermal Il-33f/f K5Cre S6). what specific phenotype, thickening 5a) 5b). 5c vivo As 5e, KC nucleus, negative (white arrow), active stimuli. informed 5f), potentiality being regulated Next, primary cultured molecules. Recombinant 5g h). supernatant (PBS control treatment) survival rate 5i j). homogenate S7a–d). treating obtained S7e–h). Thus, IL-33?pretreated conditional medium phosphorylation molecules, p38, c-Jun N-terminal kinase, extracellular signal–regulated upregulated abolished addition anti–IL-33?neutralizing 5k). effects KCs, hours analysis. stimulation, Ccl2, monocytes, cells; Cxcl1, Cxcl2, Cxcl15, recruiting neutrophils; Vegf, growth 6a). TNF-?; CXCL1, CXCL2, CXCL8; CCL2; CCL20, key 17 S100A7/?-defensin 6b). profiles detected RNA sequencing explore targets Signaling enrichment Ras, Hippo, 6c), Ccl20, Ccl7, Tab2, so 6d), among Ccl20 Ccl2 MAPKs family members, P38 factors NF-?B transducer activator (STAT)3. p65 STAT3 apparently 5–10 minutes, STAT1 6e). identify upstream tyrosine kinase STAT3, most Jak1, Jak2, Jak3, TYK2, detected. TYK2 unchanged 6f). reversed Jak2-specific inhibitor 6g). self-regulation underlying pathways, inhibitors used treat IL-33–pretreated promoted representative genes, 6h). inhibited either Jak2 6i). (data shown). MAPK thus psoriasis-associated molecule controversial. Athari Scholar assessed necessity they reported independent our alleviated discrepancy paper work caused differences age, observation time points studies. Given presented self-relief 5–6 (Han 2019Han Mora Huard da Silva P. 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