The Journal of allergy and clinical immunology | 2019
TSLP epigenetically upregulates FcRγ-related receptors on APCs and induces TH2/TH17 polarization via dectin-2.
Abstract
BACKGROUND\nFc receptor gamma subunit (FcRγ)-related receptors expressed on antigen-presenting cells (APCs) enhance allergen sensitization and allergic inflammation. DNA demethylation of the Fc fragment of IgE receptor Ig (FCER1G) leads to FcRγ and FcεR1 overexpression on monocytes from patients with atopic dermatitis (AD).\n\n\nOBJECTIVE\nWe investigated epigenetic mechanisms underlying FCER1G demethylation and upregulation of FcRγ-related receptors on APCs and the consequent impact on allergic responses.\n\n\nMETHODS\nEffects of thymic stromal lymphopoietin (TSLP) on the expression of FcRγ and its related receptors, and methylation or hydroxymethylation of FCER1G in human monocytes were assessed. Recruitment of ten-eleven translocation protein 2 (TET2) to FCER1G by TSLP-activated phospho-signal transducer and activator of transcription 5 (pSTAT5) was evaluated. Effects of TSLP on the expression of FcRγ-related receptors and costimulatory receptors on monocyte-derived dendritic cells (MoDCs) and ability of DCs to take-up ovalbumin were analyzed. TSLP-induced TH polarization and related cytokine production were also analyzed.\n\n\nRESULTS\npSTAT5 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 MoDC 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 upon neutralization with a dectin-2 antibody.\n\n\nCONCLUSIONS\nTSLP 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.