Janus kinase inhibitors display broad anti-itch properties: A possible link through the TRPV1 receptor Tomoki Fukuyama, DVM, PhD, Joy Rachel Ganchingco,

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Janus kinase inhibitors display broad anti-itch properties: A possible link through the TRPV1 receptor Tomoki Fukuyama, DVM, PhD, Joy Rachel Ganchingco, DVM, Santosh K. Mishra, PhD, Thierry Olivry, DrVet, PhD, Ignacy Rzagalinski, MSc, Dietrich A. Volmer, PhD, Wolfgang Bäumer, DrMedVet, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 1, Pages 306-309.e3 (July 2017) DOI: 10.1016/j.jaci.2016.12.960 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Inhibitory effect of oclacitinib and tofacitinib on the pruritogen-induced Ca2+ increase in mouse sensory neurons and pruritogen-evoked scratching/wiping behavior in mice. A and B, Percentage of several pruritogen-induced responses in mouse DRG neurons pretreated in vitro with vehicle only, oclacitinib, or tofacitinib for 1 minute. Numbers of neurons tested are given in parentheses. *P < .05 and **P < .01 (Fisher exact test) versus the vehicle-only group. In Fig 1, B, example recordings show cytosolic Ca2+ increase (ratio, 340ex/380ex) for a single region of interest taken every 100 ms. C, Scratching or wiping (capsaicin) response after oral administration of JAK inhibitors to several pruritogens in mice. Results are expressed as means ± 1 SDs (n = 8 per group). *P < .05 and **P < .01 (Dunnett multiple comparison test) versus the vehicle-only control group. Journal of Allergy and Clinical Immunology 2017 140, 306-309.e3DOI: (10.1016/j.jaci.2016.12.960) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Inhibitory effect of tofacitinib on pruritogen-induced Ca2+ increase in TRPV1 knockout (KO) mouse sensory neurons, pruritogen-evoked scratching/wiping behavior in the TRPV1 KO mouse, and TDI-induced chronic itch in the BALB/c mouse. A, Percentage of several pruritogen-induced responses in TRPV1 KO mouse DRG neurons pretreated in vitro with vehicle only or tofacitinib for 1 minute. Numbers of neurons tested are given in parentheses. *P < .05 and **P < .01 (Fisher exact test) versus the vehicle-only group. B, Scratching or wiping (capsaicin) response after oral administration of tofacitinib to several pruritogens in TRPV1 KO mice. Results are expressed as means ± 1 SDs (n = 6 per group). *P < .05 and **P < .01 (Student t test) versus the vehicle-only control group. C, Expression of TRPV1 receptor–positive neurons in DRGs from mice with TDI-induced chronic itch. Results are expressed as means ± SDs (n = 6 per group). *P < .05 (Student t test) versus the control group. D, Immunohistochemistry of DRGs from the TDI-induced chronic itch model demonstrates increased number of cells positive for TRPV1 receptors. E, Scratching response after topical application of tofacitinib during the challenge phase of TDI-induced chronic allergic dermatitis. Results are expressed as means ± 1 SDs (n = 6 per group). **P < .01 (Student t test) versus the vehicle-only control group. Journal of Allergy and Clinical Immunology 2017 140, 306-309.e3DOI: (10.1016/j.jaci.2016.12.960) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Inhibitory effect of JAK inhibitors on capsaicin responses in TRPV1-transfected AD293 cells and imaging of drug binding to TRPV1. A, Inhibitory effect of oclacitinib and tofacitinib on capsaicin-induced Ca2+ increase in TRPV1-transfected AD293 cells. **P < .01 (Fisher exact test) versus the vehicle-only control group. B, Visualization of TRPV1 by using SDS-PAGE after immunoprecipitation. Traces of the JAK inhibitors were found at the TRPV1 band (<100 kDa). C, Comparison of the average signal intensities of tofacitinib from mock- or TRPV1-transfected cells acquired from different SDS-PAGE bands (100-75 kDa and <15 kDa). Average signal intensities were obtained from MALDI-FTICR mass spectra of 5 different MALDI spots (16 scans averaged within one spot) after removing outliers (Grubbs and Dixon tests for n = 5 at the 95% confidence level). Bars represent SDs. D, Mass spectra from MALDI–mass spectrometric analyses of oclacitinib- or tofacitinib-treated TRPV1-transfected AD293 cells. Journal of Allergy and Clinical Immunology 2017 140, 306-309.e3DOI: (10.1016/j.jaci.2016.12.960) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions