@article{mishra_wheeler_pitake_ding_jiang_fukuyama_paps_ralph_coyne_parkington_et al._2020, title={Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch}, volume={31}, ISSN={["2211-1247"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85082772179&partnerID=MN8TOARS}, DOI={10.1016/j.celrep.2020.03.036}, abstractNote={Chronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin αVβ3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and genetic approaches, we inhibited the function of neuronal integrin αVβ3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD-causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch.}, number={1}, journal={CELL REPORTS}, author={Mishra, Santosh K. and Wheeler, Joshua J. and Pitake, Saumitra and Ding, Huiping and Jiang, Changyu and Fukuyama, Tomoki and Paps, Judy S. and Ralph, Patrick and Coyne, Jacob and Parkington, Michelle and et al.}, year={2020}, month={Apr} }
 @article{ehling_fukuyama_ko_olivry_bäumer_2019, title={Neuromedin B Induces Acute Itch in Mice via the Activation of Peripheral Sensory Neurons}, volume={99}, ISSN={0001-5555}, url={http://dx.doi.org/10.2340/00015555-3143}, DOI={10.2340/00015555-3143}, abstractNote={Neuromedin B is expressed in nociceptive and itch-sensitive dorsal root ganglia neurons, but its peripheral pruritogenic potential is not well described. The potential of neuromedin B as a pruritogen and pro-inflammatory peptide in the skin was tested in vivo in an acute model in mice and monkeys as well as an allergic dermatitis model in mice. To identify the underlying mechanisms in vitro real time PCR analysis for neuromedin B and its receptor expression in murine mast cells and dorsal root ganglia as well as functional calcium imaging in the ganglia was applied. Neuromedin B induces itch when injected intradermally, and the peripheral signal is likely transmitted through the activation of dorsal root ganglia. Thus, neuromedin B could be an interesting new therapeutic target for peripheral processing of itch at the level of sensory neurons.}, number={6}, journal={Acta Dermato Venereologica}, publisher={Acta Dermato-Venereologica}, author={Ehling, S and Fukuyama, T and Ko, M and Olivry, T and Bäumer, W}, year={2019}, pages={587–893} }
 @misc{fukuyama_ganchingco_mishra_olivry_rzagalinski_volmer_baeumer_2017, title={Janus kinase inhibitors display broad anti-itch properties: A possible link through the TRPV1 receptor}, volume={140}, ISSN={["1097-6825"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85013487374&partnerID=MN8TOARS}, DOI={10.1016/j.jaci.2016.12.960}, abstractNote={Janus kinase (JAK) inhibitors are being proposed for the treatment of cancer and inflammatory diseases, such as atopic dermatitis. Their mechanism of action, especially that to reduce itch, remains speculative. The JAK inhibitor oclacitinib is currently approved for the treatment of lesions and pruritus in dogs with atopic dermatitis,1,2 whereas tofacitinib is under clinical development for the treatment of the homologous human disease (https://www.clinicaltrials.gov/ct2/show/NCT02001181). In rodent and canine models of allergic dermatitis and in human patients with psoriasis and atopic dermatitis, the antipruritic effect of JAK inhibitors is rapidly visible.}, number={1}, journal={JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY}, author={Fukuyama, Tomoki and Ganchingco, Joy Rachel and Mishra, Santosh K. and Olivry, Thierry and Rzagalinski, Ignacy and Volmer, Dietrich A. and Baeumer, Wolfgang}, year={2017}, month={Jul}, pages={306-+} }
 @article{fukuyama_ganchingco_baumer_2017, title={Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib}, volume={794}, ISSN={["1879-0712"]}, DOI={10.1016/j.ejphar.2016.11.020}, abstractNote={The janus kinase-inhibitor oclacitinib is licensed for the control of pruritus associated with allergic skin diseases in dogs. Strikingly, it has been clinically reported that abrupt withdrawal of oclacitinib leads to a rebound pruritus in dogs. Therefore, the primary objective of this study was to mimic the rebound phenomenon of oclacitinib using a chronic pruritic mouse model of allergic contact dermatitis. Chronic allergic contact dermatitis was induced by repetitive toluene-2,4-diisocyanate (TDI) challenge in BALB/c mice. Oclacitinib was orally administered twice daily at 45mg/kg for 7 days, with concurrent TDI challenge, and then treatment of oclacitinib was abruptly discontinued. Scratching bouts following TDI challenge were evaluated to day 15. Additionally, dorsal root ganglia (DRG) and affected skin were isolated from mice receiving oclacitinib and from mice 24h after oclacitinib withdrawal and were used to determine pruritogen induced Ca2+ signals in sensory neurons, the number of activated dendritic cells (DCs) within DRG, and the cytokine profiles of affected skin. Mice treated with oclacitinib showed a significant decrease in scratching bouts during treatment, then following abrupt withdrawal scratching bouts were significantly increased. Furthermore, following abrupt withdrawal more DRG neurons were activated by pruritogenic cytokines, TNFα positive DCs were significantly increased, and affected skin revealed a significant increase of TNFα and TSLP. In conclusion, while oclacitinib significantly reduced itch during treatment the abrupt withdrawal led to a rapid rebound phenomenon which can be explained by an increase in pruritogenic cytokines and fast peripheral sensitization.}, journal={EUROPEAN JOURNAL OF PHARMACOLOGY}, author={Fukuyama, Tomoki and Ganchingco, Joy Rachel and Baumer, Wolfgang}, year={2017}, month={Jan}, pages={20–26} }
 @article{cruse_yin_fukuyama_desai_arthur_baumer_beaven_metcalfe_2016, title={Exon skipping of Fc epsilon RI beta eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy}, volume={113}, ISSN={["0027-8424"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85002784626&partnerID=MN8TOARS}, DOI={10.1073/pnas.1608520113}, abstractNote={Significance
          We identified an innovative use for the technique of antisense oligonucleotide-mediated exon skipping to specifically target and down-regulate IgE receptor expression in mast cells. Exon skipping is typically used as part of personalized medicine, where a mutant exon is skipped after sequencing the patients’ affected genes. Our approach, however, targets a nonmutated gene and an exon that is critical for surface IgE receptor expression. It does not require a personalized approach with genetic sequencing or multiple iterations of oligonucleotides that would require clinical trials. Furthermore, the diseases to be treated with this technology are ideal for local delivery of the oligonucleotides by aerosols or topical cream formulations.}, number={49}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Cruse, Glenn and Yin, Yuzhi and Fukuyama, Tomoki and Desai, Avanti and Arthur, Greer K. and Baumer, Wolfgang and Beaven, Michael A. and Metcalfe, Dean D.}, year={2016}, month={Dec}, pages={14115–14120} }
 @article{stover_fukuyama_young_daniele_oberley_crapo_baeumer_2016, title={Topically applied manganese-porphyrins BMX-001 and BMX-010 display a significant anti-inflammatory response in a mouse model of allergic dermatitis}, volume={308}, ISSN={["1432-069X"]}, DOI={10.1007/s00403-016-1693-0}, abstractNote={In this study, we topically administered two antioxidant compounds, the manganese-porphyrin-derivatives BMX-001 and BMX-010, in a mouse model of allergic dermatitis and compared the efficacy for reduction of itch and inflammation. In vitro effects of BMX-001 and BMX-010 on keratinocytes, bone marrow derived dendritic cells (BMDCs) and T-cells were initially analysed. For assessment of scratching behaviour, BMX-001 and BMX-010 (0.01 and 0.1 %) were topically applied 16 h and/or 1 h before compound 48/80 or toluene-2,4,-diisocyanate (TDI) challenge in a TDI induced mouse dermatitis model. Additionally, assessment of allergic skin inflammation was performed in a similar manner in the TDI model. Post-treatment ear thickness was measured 24 h after TDI challenge and compared to basal values. The mice were sacrificed and the ear auricle was removed for further analysis. In vitro, both BMX substances significantly inhibited cytokine production of keratinocytes as well as of BMDC and T-cell proliferation. Topical treatment with BMX cream resulted in a significant decrease in scratching behaviour in the compound 48/80 model, but not in the TDI model. Mice treated with BMX-001 and BMX-010 showed a moderate dose dependent decrease in ear thickness, and interestingly, the concentration of the cytokines IL-1β and IL-4 in inflamed skin was reduced by 80–90 % by all treatment options. These first results suggest the potential benefit of a BMX-001 and BMX-010 cream for the treatment of allergic-inflammatory skin diseases.}, number={10}, journal={ARCHIVES OF DERMATOLOGICAL RESEARCH}, author={Stover, Kelsey and Fukuyama, Tomoki and Young, Ashlyn T. and Daniele, Michael A. and Oberley, Rebecca and Crapo, James D. and Baeumer, Wolfgang}, year={2016}, month={Dec}, pages={711–721} }
 @article{fukuyama_tschernig_qi_volmer_baumer_2015, title={Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions}, volume={764}, DOI={10.1016/j.ejphar.2015.06.060}, abstractNote={Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitised mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour.}, journal={European Journal of Pharmacology}, author={Fukuyama, T. and Tschernig, T. and Qi, Y. L. and Volmer, D. A. and Baumer, W.}, year={2015}, pages={278–282} }
 @article{fukuyama_ehling_cook_baeumer_2015, title={Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis}, volume={354}, ISSN={["1521-0103"]}, DOI={10.1124/jpet.115.223784}, abstractNote={The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow–derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.}, number={3}, journal={JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS}, author={Fukuyama, Tomoki and Ehling, Sarah and Cook, Elizabeth and Baeumer, Wolfgang}, year={2015}, month={Sep}, pages={394–405} }