Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting TH17 cell polarization - 04/05/19
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
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). |
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| 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. |
Vol 143 - N° 5
P. 1878-1891 - mai 2019 Retour au numéro
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