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Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting TH17 cell polarization - 04/05/19

Doi : 10.1016/j.jaci.2018.09.032 
Norimasa Tamehiro, PhD a, , Kyoko Nishida, MS a, b, Yu Sugita, MD a, Kunihiro Hayakawa, PhD a, Hiroyo Oda, PhD a, Takeshi Nitta, PhD a, Miwa Nakano, PhD c, Akiko Nishioka d, Reiko Yanobu-Takanashi, MS e, Motohito Goto, BS e, Tadashi Okamura, DVM, PhD e, f, Reiko Adachi, PhD g, Kazunari Kondo, PhD g, Akimichi Morita, MD, PhD d, Harumi Suzuki, PhD a,
a Department of Immunology and Pathology, National Center for Global health and Medicine, Chiba, Japan 
c Communal laboratory, National Center for Global health and Medicine, Chiba, Japan 
e Department of Laboratory Animal Medicine, National Center for Global health and Medicine, Chiba, Japan 
f Department of Infectious Diseases, Research Institute, National Center for Global health and Medicine, Chiba, Japan 
b Department of Immunology, Tokyo Medical and Dental University, Tokyo, Japan 
d Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 
g Department of Biochemistry, National Institute of Health Sciences, Kawasaki, Japan 

Corresponding author: Harumi Suzuki, PhD, Department of Immunology and Pathology, Research Institute, National Center for Global health and Medicine, Chiba 272-8516, Japan.Department of Immunology and PathologyResearch InstituteNational Center for Global health and MedicineChiba272-8516Japan

Abstract

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 TH17 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 γt. The consequential increase in IL-17 and IL-22 production induced T cells to differentiate into TH17 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 TH17 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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Graphical abstract




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Key words : Psoriasis, T cell, TH17, IL-22 binding protein, retinoic acid–related orphan receptor γt, Nr2f6, T-cell receptor signaling

Abbreviations used : cLN, DC, EV, Foxp3, GFP, IL-22BP, LFA-1, Nr2f6, PASI, Rag, RhoH, ROR, STAT, γδT17, TC1, TCR, Ubr5, ZAP


Plan


 Supported by grants from the National Center for Global Health and Medicine (25-103 and 26-106).
 Disclosure of potential conflict of interest: N. Tamehiro has received grant support from the Ministry of Education, Culture, Sports, Science and Technology in Japan; the Uehara Memorial Foundation; the Takeda Science Foundation; and the Suzuki Foundation. T. Okamura has received grants from the National Center for Global Health and Medicine. H. Suzuki has received grants from the National Center for Global Health and Medicine and the Ministry of Education, Culture, Sports, Science and Technology in Japan. The rest of the authors declare that they have no relevant conflicts of interest.


© 2018  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 143 - N° 5

P. 1878-1891 - mai 2019 Retour au numéro
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