Thymic stromal lymphopoietin epigenetically upregulates Fc receptor γ subunit-related receptors on antigen-presenting cells and induces TH2/TH17 polarization through dectin-2.

Abstract

BACKGROUND:

Fc receptor γ subunit (FcRγ)-related receptors expressed on antigen-presenting cells (APCs) enhance allergen sensitization and allergic inflammation. DNA demethylation of the high-affinity IgE receptor γ subunit gene (FCER1G) leads to FcRγ and FcεRI overexpression on monocytes from patients with atopic dermatitis.

OBJECTIVE:

We investigated epigenetic mechanisms underlying FCER1G demethylation and upregulation of FcRγ-related receptors on APCs and the consequent effect on allergic responses.

METHODS:

Effects of thymic stromal lymphopoietin (TSLP) on expression of FcRγ and its related receptors and methylation or hydroxymethylation of FCER1G in human monocytes were assessed. Recruitment of ten-eleven translocation protein (TET) 2 to FCER1G by TSLP-activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) was evaluated. Effects of TSLP on expression of FcRγ-related receptors and costimulatory receptors on monocyte-derived dendritic cells (DCs) and the ability of DCs to take up ovalbumin were analyzed. TSLP-induced TH polarization and related cytokine production were also analyzed.

RESULTS:

pSTAT5 activation by TSLP resulted in TET2 recruitment to FCER1G, leading to FCER1G demethylation and subsequent upregulation of FcRγ-related receptors on monocytes. TSLP not only stimulated monocyte-derived DC maturation but also maintained their allergen uptake ability, likely through maintenance and upregulation of FcRγ-related receptors. Allergen sensitization and upregulation of TH2/TH17-related cytokines contributed to TSLP-DC-induced TH2/TH17 polarization. The latter was attenuated on neutralization with a dectin-2 antibody.

CONCLUSIONS:

TSLP mediated upregulation of FcRγ-related receptors on APCs through activation of pSTAT5, which recruited TET2 to induce FCER1G demethylation. TSLP-induced allergic TH2/TH17 polarization likely depends on dectin-2-mediated allergen sensitization and upregulation of TH2/TH17-related cytokines.

• Authors: Yunsheng Liang, Bihui Yu, Junchen Chen, Haijin Wu, Yingping Xu, Bin Yang, Qianjin Lu
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 144 Issue 4 Pg. 1025-1035.e7 (10 2019) ISSN: 1097-6825 [Electronic] United States
• PMID: 31251950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CLEC6A protein, human
• Cytokines
• FCER1G, human
• Lectins, C-Type
• Receptors, Fc
• TSLP protein, human

Topics

• Antigen-Presenting Cells (immunology)
• Cytokines (immunology, metabolism)
• DNA Methylation
• Dermatitis, Atopic (immunology, metabolism)
• Epigenesis, Genetic
• Humans
• Lectins, C-Type (immunology)
• Receptors, Fc (biosynthesis, immunology)
• Signal Transduction (immunology)
• Th17 Cells (immunology)
• Th2 Cells (immunology)
• Transcriptional Activation (immunology)
• Up-Regulation