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

J Allergy Clin Immunol. 2019 May;143(5):1878-1891. doi: 10.1016/j.jaci.2018.09.032. Epub 2018 Oct 17.

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.

Keywords: IL-22 binding protein; Nr2f6; Psoriasis; T cell; T(H)17; T-cell receptor signaling; retinoic acid–related orphan receptor γt.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Chronic Disease
  • Dermatitis / drug therapy
  • Dermatitis / genetics
  • Dermatitis / metabolism*
  • Disease Models, Animal
  • Humans
  • Interleukin-22
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Psoriasis / drug therapy
  • Psoriasis / genetics
  • Psoriasis / metabolism*
  • Receptors, Interleukin / therapeutic use
  • Repressor Proteins / genetics
  • Th17 Cells / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*

Substances

  • IL22RA2 protein, human
  • Interleukins
  • Nr2f6 protein, mouse
  • Receptors, Interleukin
  • Repressor Proteins
  • RhoH protein, mouse
  • Transcription Factors
  • UBR5 protein, mouse
  • Ubiquitin-Protein Ligases
  • rho GTP-Binding Proteins