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Single cell transcriptomics reveal type-2 inflammatory gene regulation in airway epithelium driven by allergen-specific immunotherapy

ABSTRACT: Background: Airway epithelium in patients with allergic airway disease actively releases and is subjected to the influence of type-2 cytokines with observable changes in basal epithelial cells. Symptoms that grass pollen-allergic patients experience due to this priming can be controlled by allergen-specific immunotherapy (AIT). However, the impact of AIT on type-2 related mediators of airway epithelial cells is unknown. Methods: Protein levels of type-2 cytokines in nasal secretions of grass pollen-allergic patients were analyzed during 3-year AIT-regimen using multiplex-ELISA. Source and IL-4-dependence of type-2 cytokines were examined in IL-4-primed primary ALI cultures using single-cell transcriptomics. Results: Type-2 cytokines CCL-26 and POSTN oscillated seasonally, derived from basal epithelial cells and were induced by IL-4-priming. In contrast, TSLP and IL-33 derived from basal cells, albeit independently of IL-4. POSTN and IL-24 nasal levels changed corresponding to 3-year AIT progression. Four characteristic epithelial type-2 cytokines stood out: IL-33 changed independent of season, IL-4-exposure, or AIT; CCL-26 was triggered upon IL-4-priming and was induced during pollen season, but not influenced by AIT; IL-24 decreased following three years of AIT; and POSTN, which was increased in IL-4-primed basal epithelial cells and oscillated during pollen season, also responded to long-term AIT. Conclusions: Atopic reprogramming of type-2 epithelial cytokines seems to persist despite long-term AIT, which may be one mechanism explaining why AIT only restores allergen tolerance for seven to ten years. Type-2 related epithelial cytokines are differentially expressed which may relate to the distinct expression of basal as opposed to differentiated secretory or ciliated epithelial cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203248 | GEO | 2023/03/31

REPOSITORIES: GEO

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Project description:Introduction Disruption of the epithelial barrier can induce eosinophilic esophagitis (EoE), a TH2-mediated food- and aeroallergen associated chronic inflammatory disease 1, 2. The expression of IL-20 subfamily cytokines, IL-19, IL-20 and IL-24, is increased in TH2-mediated diseases, yet their function in EoE is unknown. Methods Combining RNA-sequencing (RNA-seq) and proteome analysis, we have examined the effects of the IL-20 subfamily on esophageal epithelial cells using patient-derived organoids and an experimental EoE mouse model. Results When stimulated with IL-20 subfamily cytokines patient-derived esophageal organoids showed decreased expression of Filaggrin (FLG) and Filaggrin 2 (FLG2) responsible for epithelial cornification. In agreement, EoE patients with active inflammation showed elevated IL-20 subfamily cytokines and decreased FLG and FLG2 expression. Topical corticosteroid treatment in EoE patients restored filaggrin expression, while reducing IL-20 subfamily cytokines. Abolishment of IL-20 subfamily signalling in Il20R2-/- animals attenuated experimental EoE in an OVA-induced mouse model. In the esophageal keratinocyte cell line, KYSE-180, we identified IL-20 subfamily-induced STAT3 and MAPK (ERK1/2) pathway activation. However, Stat3fl/flKrt5cre mice with an epithelium specific deletion of Stat3 developed exacerbated experimental EoE with a pronounced decrease of Flg2. In line, combined stimulation of patient-derived esophageal organoids with IL-20 subfamily cytokines and pharmacological inhibition of STAT3 resulted in aggravated decrease of FLG and FLG2. In addition, pharmacological STAT3 inhibition resulted in reduced transepithelial electrical resistance (TEER) and increased macromolecular flux in patient-derived air liquid interface (ALI) cultures. Whereas, inhibition of the MAPK (ERK1/2) pathway hampered IL-20 subfamily induced TEER reduction and paracellular flux increment. Finally, MAPK (ERK1/2) inhibitor treatment reduced infiltrating CD45+ immune cells in the esophagus and alleviated experimental EoE in mice. Conclusion We discovered a novel regulatory function of the IL-20 subfamily for epithelial barrier integrity. Aberrant IL-20 subfamily signaling disturbs the epithelial barrier function, while abrogation of IL-20 subfamily and ERK1/2 signaling restores epithelial integrity and attenuates experimental EoE. Therefore, we propose that targeting the IL-20 subfamily pathway could present a novel therapeutic strategy for EoE treatment.

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Single cell transcriptomics reveal type-2 inflammatory gene regulation in airway epithelium driven by allergen-specific immunotherapy

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