Thymic stromal lymphopoietin epigenetically upregulates Fc receptor γ subunit-related receptors on antigen-presenting cells and induces T<sub>H</sub>2/T<sub>H</sub>17 polarization through dectin-2.
basic_science · Level V
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- Record sourced from PubMed, PMID 31251950.
- Also identified by DOI 10.1016/j.jaci.2019.06.011.
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Abstract
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. We investigated epigenetic mechanisms underlying FCER1G demethylation and upregulation of FcRγ-related receptors on APCs and the consequent effect on allergic responses. 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<sub>H</sub> polarization and related cytokine production were also analyzed. 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<sub>H</sub>2/T<sub>H</sub>17-related cytokines contributed to TSLP-DC-induced T<sub>H</sub>2/T<sub>H</sub>17 polarization. The latter was attenuated on neutralization with a dectin-2 antibody. TSLP mediated upregulation of FcRγ-related receptors on APCs through activation of pSTAT5, which recruited TET2 to induce FCER1G demethylation. TSLP-induced allergic T<sub>H</sub>2/T<sub>H</sub>17 polarization likely depends on dectin-2-mediated allergen sensitization and upregulation of T<sub>H</sub>2/T<sub>H</sub>17-related cytokines.
Medical subject headings
- Antigen-Presenting Cells
- Cytokines
- Dermatitis, Atopic
- Lectins, C-Type
- Receptors, Fc