Temporal Genome Expression Profile Analysis During T-cell-Mediated Colitis: Identification of Novel Targets and Pathways

Abstract

T cells critically regulate IBD with T cell dependent experimental colitis models gaining favor in identifying potential pathogenic mechanisms; yet, limited understanding of specific pathogenic molecules or pathways still exists. In this study, we sought to identify changes in whole genome expression profiles using the CD4CD45Rbhi T cell transfer colitis model compared to genome expression differences from Crohn's disease tissue specimens. Colon tissue was used for histopathological and genome expression profiling analysis at 0, 2, 4, or 6 weeks after adoptive T cell transfer. We identified 1,775 genes that were significantly altered during disease progression with 361 being progressively down regulated and 341 progressively up regulated. Gene expression changes were validated by qRT-PCR confirming genome expression analysis data. Differentially expressed genes were clearly related to inflammation/immune responses but also strongly associated with metabolic, chemokine signaling, Jak-STAT signaling, and angiogenesis pathways. Ingenuity network analysis revealed 25 unique network associations that were associated with functions such as antigen presentation, cell morphology, cell-to-cell signaling and interaction, as well as nervous system development and function. Moreover, many of these genes and pathways were similarly identified in Crohn's disease specimens. These findings reveal novel, complex, and dynamic changes in gene expression that may provide useful targets for future therapeutic approaches.

Identification of a Novel Substance P–Neurokinin-1 Receptor MicroRNA-221-5p Inflammatory Network in Human Colonic Epithelial Cells

“…IL-6R is implicated in cytokine-cytokine receptor signaling that involves the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathways, known to be dysregulated in T-cell-mediated, and DSS- and TNBS-induced colitis. 20 , 44 , 45 Additionally, the JAK-STAT pathway is involved in the pathogenesis of UC, 46 whereas treatment with antibodies against IL-6R attenuates immune-mediated and chemically induced colitis. 47 …”

“…The threshold cycle (Ct) value formula was used to calculate the relative expression of selected miRNAs, as we previously reported elsewhere. 20 …”

Application of Comparative Transcriptional Genomics to Identify Molecular Targets for Pediatric IBD

“…In the DSS-colitis model, there were 1609 genes that were significantly altered during the colitis development, with 501 progressively up-regulated genes and 173 progressively down-regulated genes ( 7 ). In the T-cell transfer colitis model, there were 1775 gene expressions that were significantly changed, with 341 progressively up-regulated genes and 361 progressively down-regulated genes ( 6 ). The two sets of microarray data were obtained by using the same platform, Mouse Genome 430 2.0 Array (Affymetrix), which provided the most comprehensive annotated coverage of the mouse genome, composing of over 34,000 well-characterized mouse genes.…”

“…Although the microarray assay has been performed on pediatric IBD, there is no comprehensive genome transcription analysis for pediatric UC or CD. Here, we performed transcriptome analysis using two sets of pediatric IBD microarray data ( 4 , 5 ), T-cell transfer colitis model microarray data ( 6 ), and dextran sodium sulfate (DSS)-induced colitis microarray data ( 7 ) generated from our laboratory and deposited in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database. Network and promoter analysis was performed to identify differentially expressed genes in the inflamed colon tissue from pediatric IBD patients versus experimental animal models.…”

Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2 related disease

“…We also compared the intersections between COVID-19 associated genes and those associated with three different murine models of intestinal injury or inflammation. We observed a significant overlap between genes up-regulated with COVID-19 response in the NHBE lung model with genes upregulated in either a 1) Dextran Sodium Sulfate (DSS) induced intestinal injury model 35 ; 2) TNBS-intestinal injury model 36 , especially two days post TNBS administration or 3) adoptive T cell transfer colitis model 37 following a 6-week time period (ie W0<W2<W4<W6). Some examples of genes found commonly up-13 regulated amongst the 3 IBD-mouse models and NHBE-COVID-19 response included C3, IFITM3, IL1B, S100A9, TGM2 (transglutaminase 2) and PLAUR (plasminogen activator, urokinase receptor) (Table S22).…”