Thromboxane A2 facilitates IL-17A production from Vγ4+ γδ T cells and promotes psoriatic dermatitis in mice Yuri Ueharaguchi, MD, Tetsuya Honda, MD,

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Presentation transcript:

Thromboxane A2 facilitates IL-17A production from Vγ4+ γδ T cells and promotes psoriatic dermatitis in mice Yuri Ueharaguchi, MD, Tetsuya Honda, MD, PhD, Nobuhiro Kusuba, MD, Sho Hanakawa, MSc, Akimasa Adachi, MD, Yu Sawada, MD, PhD, Atsushi Otsuka, MD, PhD, Akihiko Kitoh, MD, PhD, Teruki Dainichi, MD, PhD, Gyohei Egawa, MD, PhD, Chisa Nakashima, MD, PhD, Saeko Nakajima, MD, PhD, Teruasa Murata, MD, PhD, Sachiko Ono, MD, PhD, Makoto Arita, PhD, Shuh Narumiya, MD, PhD, Yoshiki Miyachi, MD, PhD, Kenji Kabashima, MD, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 2, Pages 680-683.e2 (August 2018) DOI: 10.1016/j.jaci.2018.01.054 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TP-deficient mice exhibit reduced inflammation in an IMQ-induced psoriasis model. A, The amount of TxB2 (a stable metabolite of TxA2), PGE2, PGD2, PGF2α, and 6ketoPGF2α (a stable metabolite of PGI2) in the ear skin determined by LC-MS/MS–based mediator lipidomics. Ear skin was treated with IMQ for the indicated period (n = 3 for each point). B, The mRNA expression of TxA2 synthase (Tbxas) and TxA2 receptor (Tbxa2r; TP) in the ear skin 7 days after treatment with IMQ analyzed by RT-PCR (n = 3-4). Data are representative from 3 independent experiments. C, The mRNA expression of TBXAS and TBXA2R in the skin of patients with psoriasis and healthy controls (control: n = 4, patients with psoriasis: n = 12). D, Time course of ear-swelling responses in WT mice and TP-deficient (TP−/−) mice treated with IMQ for 7 days (n = 4). E, Representative images of hematoxyline and eosine–stained skin sections from WT mice and TP-deficient mice 7 days after IMQ treatment. Scale bar = 100 μm. F, The number of neutrophils, Vγ4+ γδ T cells, and Vγ4− γδ T cells in the skin 7 days after IMQ treatment analyzed by flow cytometry (n = 3-5). Data are representative of at least 3 independent experiments. Results are expressed as the mean ± SEM. ∗P < .05. Journal of Allergy and Clinical Immunology 2018 142, 680-683.e2DOI: (10.1016/j.jaci.2018.01.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TP signaling facilitates IL-17A production from Vγ4+ γδ T cells. A, mRNA expression of Il23a, Il17a, and Il22 in the skin 3 days after IMQ treatment analyzed by RT-PCR. The expression level in the skin of WT mice without IMQ treatment is set as 1, and the expression is shown as fold changes. B and C, Flow cytometric analysis of the percentage of IL-17A–producing Vγ4+ γδ T cells in the skin of WT mice and TP-deficient (TP−/−) mice 5 days after IMQ treatment analyzed by flow cytometry (n = 4-5). Representative panels are shown in Fig 2, B. D, The mRNA expression of TP and Tbxas in DCs, Vγ4+ γδT cells, and Vγ4− γδT cells analyzed by RT-PCR. E, Effect of I-BOP (TP agonist) on IL-17A production from Vγ4+ γδ T cells with or without recombinant IL-23 (rIL-23) stimulation in vitro. Intracellular staining for IL-17A was analyzed by flow cytometry. F and G, Effects of picotamid (TXBAS inhibitor) on ear-swelling responses (Fig 2, F) and IL-17A production from Vγ4+ γδ T cells (Fig 2, G) in the psoriasis model on day 5 (n = 5). Data are representative of at least 3 independent experiments. Results are expressed as the mean ± SEM. NS, Not significant. *P < .05. Journal of Allergy and Clinical Immunology 2018 142, 680-683.e2DOI: (10.1016/j.jaci.2018.01.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Lipidomics analysis of psoriatic lesions in an IMQ-induced psoriasis model, using LC-MS/MS–based mediator lipidomics. AA, Arachdonic acids; COX, cyclooxygenase; LOX, lypoxygenase; p450, cytochrome P450. Journal of Allergy and Clinical Immunology 2018 142, 680-683.e2DOI: (10.1016/j.jaci.2018.01.054) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions