Activation of protease-activated receptor 2 leads to impairment of keratinocyte tight junction integrity Peter Nadeau, BS, Mason Henehan, BS, Anna De.

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Activation of protease-activated receptor 2 leads to impairment of keratinocyte tight junction integrity Peter Nadeau, BS, Mason Henehan, BS, Anna De Benedetto, MD Journal of Allergy and Clinical Immunology Volume 142, Issue 1, Pages 281-284.e7 (July 2018) DOI: 10.1016/j.jaci.2018.01.007 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 PAR2 activation reduced keratinocytes barrier integrity. PHKs treated with SLIGKV-NH2 (PAR2 agonist, 100 μmol/L) showed (A) significantly reduced TEER at 96 and 120 hours (mean ± SEM; *P < .01 and **P < .001; n = 9) as well as (B) reduced area under the curve of TEER measured daily from 48 to 144 hours (mean ± SEM; P = .03; n = 5). Additionally, (C) permeability to Na-fluorescein at 96-, 120-, and 144-hour time points was increased in PAR2-treated PHKs as it compared to the control (mean ± SEM; *P < .01; n = 8-9). REV, Reverse peptide. Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 PAR2 activation reduced and disrupted claudin-1 and occludin membrane staining patterns. PHKs were treated with SLIGKV-NH2 (PAR2) or with REV, representative images of costaining (n = 4 experiments) for claudin-1 (red), occludin (green), and merge images collected at 120 hours postdifferentiation are shown; 4′-6-diamidino-2-phenylindole, dihydrochloride (blue, insets). Images were acquired at some setting for each target/time points. Confocal microscope: Nikon A1RMPsi (Melville, NY) (magnification 20×). Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Reduced expression of CLDN1, OCLD, and ZO-1 at the mRNA level was observed in PAR2-treated PHKs as it compared to the control (REV); blue dotted line indicates the REV control value for each gene. Samples were collected at 72 hours postdifferentiation (mean ± SEM; *P < .05 and **P < .001; n = 7). RVU, Relative value unit. Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 PAR2 activation reduced and disrupted occludin and ZO-1 membrane staining patterns. PHKs were treated with SLIGKV-NH2 (PAR2 agonist) or with REV, representative images of 4 experiments for OCLD and ZO-1 at 96 hours postdifferentiation (red) are shown; 4′-6-diamidino-2-phenylindole, dihydrochloride (blue insets). Images were acquired at same setting for each target/time points. Confocal microscope: Nikon A1RMPsi (magnification 20×). Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Semiquantification of occludin and claudin membrane staining at 120 hours postdifferentiation was obtained using Image J (total pixel area/field). For each donor, 4 random fields (20×) were captured (mean ± SEM, *P < .05; n = 4). Confocal microscope: Nikon A1RMPsi. Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 PAR2 activation is associated in reducing keratinocyte terminal differentiation. PHKs were treated with PAR2 peptide or REV (100 μmol/L) during differentiation. All genes were measured by quantitative RT-PCR, normalized to housekeeping gene (18s), and shown as RVU fold over control. Samples were collected 72 hours postdifferentiation. (REV = 1; n = 4, mean ± SEM; *P < .05). FLG, Filaggrin; LOR, loricrin; KLK, kallikreins. Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 PAR2 activation is associated in increasing IL-8. PHKs were treated with PAR2 agonist peptide or REV (100 μmol/L) during differentiation. IL-8 was measured by ELISA in the cell culture supernatant collected 48 hours posttreatment. *P < .05. Journal of Allergy and Clinical Immunology 2018 142, 281-284.e7DOI: (10.1016/j.jaci.2018.01.007) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions