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

Yunsheng Liang; Bihui Yu; Junchen Chen; Haijin Wu; Yingping Xu; Bin Yang; Qianjin Lu

doi:10.1016/j.jaci.2019.06.011

Thymic stromal lymphopoietin epigenetically upregulates Fc receptor γ subunit-related receptors on antigen-presenting cells and induces T_H2/T_H17 polarization through dectin-2

J Allergy Clin Immunol. 2019 Oct;144(4):1025-1035.e7. doi: 10.1016/j.jaci.2019.06.011. Epub 2019 Jun 25.

Authors

Yunsheng Liang¹, Bihui Yu², Junchen Chen³, Haijin Wu⁴, Yingping Xu³, Bin Yang⁵, Qianjin Lu⁶

Affiliations

¹ Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, China. Electronic address: yunshengliang@aliyun.com.
² Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, China; Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China.
³ Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
⁴ Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, China. Electronic address: yangbin101@hotmail.com.
⁶ Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China. Electronic address: qianlu5860@csu.edu.cn.

PMID: 31251950
DOI: 10.1016/j.jaci.2019.06.011

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 T_H 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 T_H2/T_H17-related cytokines contributed to TSLP-DC-induced T_H2/T_H17 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 T_H2/T_H17 polarization likely depends on dectin-2-mediated allergen sensitization and upregulation of T_H2/T_H17-related cytokines.

Keywords: Atopic dermatitis; DNA demethylation; FcRγ-related receptors; IL-25; IL-33; T(H)2/T(H)17 polarization; allergen uptake; dectin-2; signal transducer and activator of transcription 5; ten-eleven translocation protein 2; thymic stromal lymphopoietin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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