2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells
FRONTIERS IN IMMUNOLOGY
Authors: Le, Stephanie T.; Merleev, Alexander A.; Luxardi, Guillaume; Shimoda, Michiko; Adamopoulos, Lannis E.; Tsoi, Lam C.; Wang, Jenny Z.; Alexanian, Claire; Raychaudhuri, Siba P.; Hwang, Samuel T.; Gudjonsson, Johann; Marusina, Alina, I; Maverakis, Emanual
Abstract
The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of 1L17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.
A Role for RUNX3 in Inflammation-Induced Expression of IL23A in Gastric Epithelial Cells
CELL REPORTS
Authors: Hor, Yit Teng; Voon, Dominic Chih-Cheng; Koo, Jason Kin Wai; Wang, Huajing; Lau, Wen Min; Ashktorab, Hassan; Chan, Shing Leng; Ito, Yoshiaki
Abstract
RUNX3 functions as a tumor suppressor in the gastric epithelium, where its inactivation is frequently observed during carcinogenesis. We identified IL23A as a RUNX3 target gene in gastric epithelial cells. This was confirmed in a series of in vitro analyses in gastric epithelial cell lines. In elucidating the underlying regulatory network, we uncovered a prominent role for the TNF-alpha/NF-kappa B pathway in activating IL23A transcription. Moreover, the activating effect of TNF-alpha was markedly augmented by the infection of Helicobacter pylori, the primary cause of human gastritis. Of note, H. pylori utilized the CagA/SHP2 pathway to activate IL23A, as well as the induction of the NOD1 pathway by iE-DAP. Importantly, RUNX3 synergized strongly with these physiologically relevant stimuli to induce IL23A. Lastly, we present evidence for the secretion of IL23A by gastric epithelial cells in a form that is distinct from canonical IL-23 (IL23A/IL12B).
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