JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 卷:143 |
Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting TH17 cell polarization | |
Article | |
Tamehiro, Norimasa1,7  Nishida, Kyoko1,5  Sugita, Yu1  Hayakawa, Kunihiro1  Oda, Hiroyo1  Nitta, Takeshi1  Nakano, Miwa2  Nishioka, Akiko6  Yanobu-Takanashi, Reiko3  Goto, Motohito3  Okamura, Tadashi3,4  Adachi, Reiko7  Kondo, Kazunari7  Morita, Akimichi6  Suzuki, Harumi1  | |
[1] Natl Ctr Global Hlth & Med, Dept Pathol & Immunol, Res Inst, Chiba 2728516, Japan | |
[2] Natl Ctr Global Hlth & Med, Communal Lab, Res Inst, Chiba, Japan | |
[3] Natl Ctr Global Hlth & Med, Dept Lab Anim Med, Res Inst, Chiba, Japan | |
[4] Natl Ctr Global Hlth & Med, Dept Infect Dis, Res Inst, Chiba, Japan | |
[5] Tokyo Med & Dent Univ, Dept Immunol, Tokyo, Japan | |
[6] Nagoya City Univ, Dept Geriatr & Environm Dermatol, Grad Sch Med Sci, Nagoya, Aichi, Japan | |
[7] Natl Inst Hlth Sci, Dept Biochem, Kawasaki, Kanagawa, Japan | |
关键词: Psoriasis; T cell; T(H)17; IL-22 binding protein; retinoic acid-related orphan receptor gamma t; Nr2f6; T-cell receptor signaling; | |
DOI : 10.1016/j.jaci.2018.09.032 | |
来源: Elsevier | |
【 摘 要 】
Background: Ras homolog gene family H (RhoH) is a membrane-bound adaptor protein involved in proximal T-cell receptor signaling. Therefore RhoH plays critical roles in the differentiation of T cells; however, the function of RhoH in the effecter phase of the T-cell response has not been fully characterized. Objective: We sought to explore the role of RhoH in inflammatory immune responses and investigated the involvement of RhoH in the pathogenesis of psoriasis. Methods: We analyzed effector T-cell and systemic inflammation in wild-type and RhoH-null mice. RhoH expression in T cells in human PBMCs was quantified by using RT-PCR. Results: RhoH deficiency in mice induced T(H)17 polarization during effector T-cell differentiation, thereby inducing psoriasis-like chronic dermatitis. Ubiquitin protein ligase E3 component N-recognin 5 (Ubr5) and nuclear receptor subfamily 2 group F member 6 (Nr2f6) expression levels decreased in RhoH-deficient T cells, resulting in increased protein levels and DNA binding activity of retinoic acid-related orphan receptor gt. The consequential increase in IL-17 and IL-22 production induced T cells to differentiate into T(H)17 cells. Furthermore, IL-22 binding protein/Fc chimeric protein reduced psoriatic inflammation in RhoH-deficient mice. Expression of RhoH in T cells was lower in patients with psoriasis with very severe symptoms. Conclusion: Our results indicate that RhoH inhibits T(H)17 differentiation and thereby plays a role in the pathogenesis of psoriasis. Additionally, IL-22 binding protein has therapeutic potential for the treatment of psoriasis.
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