SMALL INTESTINAL INFLAMMATORY CHANGES ASSOCIATED WITH EOSINOPHIL DEGRANULATION INCREASE THE SEVERITY OF PSORIATIC SKIN INFLAMMATION

초록

ntroduction: Patients with psoriasis often display elevated inci-dence of inflammatory bowel disease, indicating a link between the skin and gut immune responses. Increased intestinal permeability can exacerbate psoriasis and systemic inflammatory disease with complex pathogenesis.Objectives: We investigated the link between inflammatory re-sponses in the skin and small intestine associated with eosinophil degranulation which led to impaired intestinal barrier integrity using imiquimod (IMQ) induced mice model. Methods: Seventeen patients (mean age 40.00 ± 14.16 years) di-agnosed with psoriasis were included in the study. Control serum was collected from 10 healthy volunteers (mean age 38.30 ± 7.60 years). Serum level of CD14, zonulin were measured using ELISA. BALB/c mice received a topical dose of 62.5 mg/d IMQ cream (5%) or vehicle cream on the shaved back for 5-7 days. To assess the intestinal barrier integrity, mice treated with IMQ and admi-nistered FITC-dextran by oral gavage and checked serum level of FITC-dextran. We compared the transcriptomes in the psoriatic mice skin with those in the small intestine. Gene set enrichment analysis (GSEA) was performed. Genomic DNA was extracted from frozen stool samples. To validate the exacerbating effect of eosinophil degranulation-induced small intestinal damage on psoriatic inflammation, we evaluated the development of psoriatic dermatitis in ∆dblGATA (∆EO) mice, which lack eosinophils. To verify that granules derived from eosinophils induced damage to intestinal epithelial cells, we cultured Caco-2, human colon epithelial cells with culture supernatants from untreated or IMQ-stimulated AML14.3D10 cells, human eosinophil cell line. Dif-ferences among groups were examined for statistical significance using one-way analysis of variance (ANOVA).Results: Compared with healthy individuals, patients with pso-riasis showed increased serum levels of soluble CD14 (sCD14), calprotectin and upregulation of zonulin which are markers of increased intestinal permeability and inflammation.In IMQ-treated mice also demonstrated increased serum levels of sCD14 and calprotectin. Mice treated with IMQ and administered FITC-dextran by oral gavage displayed elevated serum levels of FITC-dextran, which suggest increased intestinal permeability in mice with psoriatic skin inflammation. Most of the significant gene ontology terms in the mice lesion skin were related with upregulation of genes, such as Cxcl5, Il23r, Cd3, and Zap70, implicated in neutrophil recruitment and Th17 differentiation. Tlr8, Tlr9, C1qb, C1qc, and Tnf were among the most highly upregulated IMQ-induced genes related to leukocyte-mediated immunity in the small intestine. Mice with psoriatic inflammation showed increased intestinal levels of eosinophil granule-derived proteins, as demonstrated by increased EPX levels in stool. Caco-2 intestinal epithelial cells treated with media containing eosinophil granule proteins exhibited signs of inflammation and damage. IMQ-induced skin and intestinal inflammatory changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by eosinophil transfer. TLR7-deficient mice did not show intestinal eosinophil degranulation and exhibited attenuated skin and small-intestinal inflammation following IMQ application.Conclusions: Our findings strongly suggest that TLR7-dependent bidirectional skin-to-gut communication in psoriatic inflammation, and that intestinal inflammatory changes can accelerate psoriasis