IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis

Abstract

ObjectiveDisruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown.DesignCombining transcriptomic, proteomic and functional analyses, we studied the importance of the IL-20 subfamily for EoE using patient-derived oesophageal three-dimensional models and an EoE mouse model.ResultsPatients with active EoE have increased expression of IL-20 subfamily cytokines in the oesophagus and serum. In patient-derived oesophageal organoids stimulated with IL-20 cytokines, RNA sequencing and mass spectrometry revealed a downregulation of genes and proteins forming the cornified envelope, including filaggrins. On the contrary, abrogation of IL-20 subfamily signalling in Il20R2−/− animals resulted in attenuated experimental EoE reflected by reduced eosinophil infiltration, lower Th2 cytokine expression and preserved expression of filaggrins in the oesophagus. Mechanistically, these observations were mediated by the mitogen-activated protein kinase (MAPK); extracellular-signal regulated kinases (ERK)1/2) pathway. Its blockade prevented epithelial barrier impairment in patient-derived air–liquid interface cultures stimulated with IL-20 cytokines and attenuated experimental EoE in mice.ConclusionOur findings reveal a previously unknown regulatory role of the IL-20 subfamily for oesophageal barrier function in the context of EoE. We propose that aberrant IL-20 subfamily signalling disturbs the oesophageal epithelial barrier integrity and promotes EoE development. Our study suggests that specific targeting of the IL-20 subfamily signalling pathway may present a novel strategy for the treatment of EoE.

Assessment of local and systemic signature of eosinophilic esophagitis (EoE) in children through multi-omics approaches

“…Plasma CXCL12 seems not increased in other eosinophil related pathology such as asthma ( 25 ), suggesting that it may be specific for EoE. Conversely, we did not observe increased concentrations of the IL-20 subfamily cytokines in plasma from our EoE children, on the opposite to recent observations in adults ( 37 ), nor increased concentrations of IL-4, IL-5, IL-13, IL-6, IL-8 or IL-1α as observed but not reproduced in ( 32 ).…”

“…It also identified other dysregulated pathways, notably major downregulation of genes involved in epithelial cell and barrier functions (SPINK6/7/8, SFTA2, EPGN, TGM3, SLURP1, ENDOU, MUC22, MUC21), in line with previous studies (35)(36)(37). The involvement of IL-20 subfamily in this epithelial barrier impairment was less evident than that observed recently in adults (37). Indeed, and despite we did evidence a high dysregulation of MAPK cascade pathway (Supplementary Table 3) and moderate upregulation of IL-19 gene, we did not evidence dysregulation of expression of genes coding for IL-20 and IL-24, nor for filaggrin or tight junctions proteins.…”

“…Transcriptomic analysis and network visualization of DE genes further highlighted the dysregulation of major immune processes, both innate and adaptive. It also identified other dysregulated pathways, notably major downregulation of genes involved in epithelial cell and barrier functions (SPINK6/7/8, SFTA2, EPGN, TGM3, SLURP1, ENDOU, MUC22, MUC21), in line with previous studies ( 35 – 37 ). The involvement of IL-20 subfamily in this epithelial barrier impairment was less evident than that observed recently in adults ( 37 ).…”

Targeting Cartilage miR-195/497 Cluster for Osteoarthritis Treatment Regulates the Circadian Clock

“…The gray value ratios of the Per2 protein/GAPDH are shown in Figure 4g. Since PD98059, an ERK inhibitor, decreased ERK 1/2 phosphorylation and inhibited the MAPK signaling pathway [34], we used PD98059 (20 μ m , 48 h) to dephosphorylate p-ERK 1/2 activated by miR-195/497. Protein extracts were subjected to immunoblotting to assess the Per2 and p16 expression.…”

Novel targets in EoE: one step forward?

“…In Gut , Kaymak and colleagues report on novel mechanisms leading to the epithelial barrier dysfunction in EoE 10. Using transcriptomic, proteomic, functional analyses of active and inactive EoE, and ex vivo organoids and mouse models, the study investigates the role of interleukin (IL)-20 subfamily members IL-19, IL-20 and IL-24.…”