MicroRNA-146a suppresses IL-17–mediated skin inflammation and is genetically associated with psoriasis Ankit Srivastava, MTech, Pernilla Nikamo, PhD,

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Presentation transcript:

MicroRNA-146a suppresses IL-17–mediated skin inflammation and is genetically associated with psoriasis Ankit Srivastava, MTech, Pernilla Nikamo, PhD, Warangkana Lohcharoenkal, PhD, Dongqing Li, PhD, Florian Meisgen, PhD, Ning Xu Landén, MD, PhD, Mona Ståhle, MD, PhD, Andor Pivarcsi, PhD, Enikö Sonkoly, MD, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 2, Pages 550-561 (February 2017) DOI: 10.1016/j.jaci.2016.07.025 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 miR-146a deficiency leads to earlier disease onset and more severe skin inflammation in the imiquimod-induced model of psoriasis. A, Timeline for topical application of imiquimod. B, Changes in ear thickness on induction of psoriasis-like skin inflammation on ears of miR-146a−/− and WT mice (n = 6). C and D, Hematoxylin and eosin staining of ear sections from miR-146a−/− and WT mice and quantification of epidermal thickening on hematoxylin and eosin–stained ears. E, IHC on ear sections from miR-146a−/− and WT mice for Ki67 (left) and quantification (right). F, Quantification of Gr-1+ cells in ear samples (n = 4). G, GSEA of epidermis of patients with psoriasis (left panel)26 or genes induced by IL-17 in keratinocytes (right panel)27,28 in imiquimod-treated miR-146a−/− mice. H, Microarray analysis of RNA from wild-type and miR-146a−/− mice after imiquimod induction. I, qPCR analyses of miR-146a, S100a7, S100a8 and S100a9, Krt16, Il1b, and Cxcr2 in mouse ear samples (n = 6). Scale bar = 100 μm. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 miR-146a suppresses the inflammatory response of keratinocytes to IL-17A. A, qPCR for Cxcl1 in primary keratinocytes of WT or miR-146a−/− mice on IL-17A treatment at 6 hours. B, GSEA for reported target genes of the IL-17 signaling pathway on transcriptome data set from human keratinocytes transfected with miR-146a mimics or scramble control (left) and heat map for selected IL-17–regulated genes (right). C, qPCR for miR-146a and IL-8 in human keratinocytes treated with 100 ng/mL IL-17A. D and E, qPCR (left) and ELISA (right) analysis of IL-8 in human keratinocytes on miR-146a overexpression/inhibition, followed by treatment with IL-17A (at the indicated doses for 6 hours [left] or 100 ng/mL for 24 hours [right]). F, Western blot analysis of phosphorylated and total p65 in keratinocytes transfected with miR-146a mimic or miR-146a inhibitor, followed by treatment with 100 ng/mL IL-17A at indicated time points. G, Immunofluorescence analysis of p65 in primary human keratinocytes transfected with miR-146a mimics or inhibitors, followed by treatment with 100 ng/mL IL-17A for 40 minutes. Scale bar = 100 μm. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 miR-146a suppresses the neutrophil chemoattractant capacity of keratinocytes. A, Summary of the experimental design. B, Chemotaxis assay of primary neutrophil granulocytes toward supernatants of primary keratinocytes treated with miR-146a inhibitor/mimic or corresponding scramble controls and thereafter treated or not with IL-17A. Plots show forward/side scatter (left) and number of migrated neutrophils (right; n = 3). *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 miR-146a–deficient mice show impaired resolution of the psoriasiform skin inflammation after discontinuation of imiquimod (IMQ) treatment. A, Timeline for topical IMQ application on mouse back skin. B, Macroscopic images of the back skin of WT and miR-146a−/− mice from days 5 to 10. C, Scoring of erythema, scaling, and skin thickness of miR-146a−/− and WT mice during the resolution phase of IMQ treatment (n = 6). D, Timeline for topical IMQ application on the back skin of miR-146a−/− and WT mice. E, Macroscopic images of back skin and hematoxylin and eosin staining of skin sections obtained from WT and miR-146a−/− mice at day 7. F, Quantification of epidermal thickness of hematoxylin and eosin–stained back skin sections (n = 4). G, IHC for Ki67 (left panel) and quantification of Ki67+ cells (right panel; n = 4). H, Quantification of Gr-1+ cells in skin samples from miR-146a−/− and WT mice (n = 4). I, qPCR for miR-146a, Il1b, Ccl20, and Cxcl1 in back skin of mice (n = 6). Scale bar = 100 μm. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 In vivo delivery of miR-146a alleviates psoriasiform skin inflammation. A, Experimental design for intradermal administration of miR-146a mimics (or scramble oligo controls) and imiquimod (IMQ) cream (Aldara) topical application on the back skin of WT mice. B, Quantification of skin thickness (left) and cumulative severity score (right; including scaling, skin thickness, and erythema) from WT mice on treatment with miR-146a mimic or controls (scrambled oligos; n = 6). C, Macroscopic imaging, hematoxylin and eosin staining (left), and quantification of epidermal thickness (right) of IMQ-treated WT mice after intradermal injection of miR-146a mimic or scramble control (n = 4). D, IHC for Ki67 (left) and quantification of Ki67+ cells (right) in epidermis (n = 4). E, Quantification of Gr-1+ cells in back skin (n = 4). F, qPCR analysis of miR-146a, Il1b, and Ly6G in samples obtained from IMQ-treated back skin of WT mice on intradermal injection of miR-146a mimic or scramble control (n = 6). Scale bar = 100 μm. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2017 139, 550-561DOI: (10.1016/j.jaci.2016.07.025) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions