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

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  1 , Bihui Yu  2 , Junchen Chen  3 , Haijin Wu  4 , Yingping Xu  3 , Bin Yang  5 , Qianjin Lu  6
Affiliations

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 et al. J Allergy Clin Immunol. 2019 Oct.

Erratum in

  • Corrigenda.
    [No authors listed] [No authors listed] J Allergy Clin Immunol. 2021 Jul;148(1):276-277. doi: 10.1016/j.jaci.2021.01.016. J Allergy Clin Immunol. 2021. PMID: 34238502 No abstract available.

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.

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.

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