Targeting of the Tec Kinase ITK Drives Resolution of T Cell–Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis

Lechner, Kristina; Mott, Stefanie; Al-Saifi, Ragheed; Knipfer, Lisa; Wirtz, Stefan; Atreya, Raja; Räth, Timo; Fraass, Tina; Winter, Zoltán; August, Avery; Luban, Jeremy; Zimmermann, Valérie S.; Weigmann, Benno

doi:10.1053/j.gastro.2021.06.072

Cited by 13 publications

(10 citation statements)

References 60 publications

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“…ITK (IL2‐induced T cell kinase) has been shown to play an important role in T cell proliferation and differentiation. Selective targeting ITK has become an attractive method for the treatment of chronic intestinal inflammation and ulcerative colitis via driving the regression of mucosal inflammation [ 39 ]. CD3D is involved in encoding protein complexes, an important part of unique chains that bind TCR and ζ chains to form tCR‐CD3 complexes that promote T cell activation [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of molecular subtypes of ischaemic stroke based on immune‐related genes and weighted co‐expression network analysis

Wei

Chen

et al. 2023

IET Systems Biology

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Immune system has been reported to play a key role in the development of ischaemic stroke (IS). Nevertheless, its exact immune‐related mechanism has not yet been fully revealed. Gene expression data of IS and healthy control samples was downloaded from Gene Expression Omnibus database and differentially expressed genes (DEGs) was obtained. Immune‐related genes (IRGs) data was downloaded from the ImmPort database. The molecular subtypes of IS were identified based on IRGs and weighted co‐expression network analysis (WGCNA). 827 DEGs and 1142 IRGs were obtained in IS. Based on 1142 IRGs, 128 IS samples were clustered into two molecular subtypes: clusterA and clusterB. Based on the WGCNA, the authors found that the blue module had the highest correlation with IS. In the blue module, 90 genes were screened as candidate genes. The top 55 genes were selected as the central nodes according to gene degree in protein–protein interactions network of all genes in blue module. Through taking overlap, nine real hub genes were obtained that might distinguish between clusterA subtype and clusterB subtype of IS. The real hub genes (IL7R, ITK, SOD1, CD3D, LEF1, FBL, MAF, DNMT1, and SLAMF1) may be associated with molecular subtypes and immune regulation of IS.

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Section: Discussionmentioning

confidence: 99%

Identification of molecular subtypes of ischaemic stroke based on immune‐related genes and weighted co‐expression network analysis

Wei

Chen

et al. 2023

IET Systems Biology

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“…However, when damage compromises barrier integrity and tolerance mechanisms fail, a complex population of immune cells within the intestinal lamina propria are exposed to the invading luminal antigens, which leads to the excessive infiltration of immune cells, as well as chemokine and cytokine production, which further exacerbate inflammation. Infiltrating cell types include neutrophils ( 16 ), dendritic cells ( 17 ), innate lymphoid cells ( 18 ), natural killer T cells ( 19 ), macrophages ( 20 ), and T cells ( 21 , 22 ). Activated immune cells communicate mutually via direct or indirect contact through the secretion of cytokines, such as tumor necrosis factor (TNF), interferon gamma (IFNγ), interleukin 1β (IL1β), IL-6, and IL-23, as well as T helper (Th) 17 cell-associated cytokines.…”

Section: Introductionmentioning

confidence: 99%

Identification of Immune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis

Kong

Chen

et al. 2022

Front. Immunol.

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BackgroundUlcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and its incidence is steadily increasing worldwide. Intestinal immune dysfunction has been identified as a central event in UC pathogenesis. However, the underlying mechanisms that regulate dysfunctional immune cells and inflammatory phenotype remain to be fully elucidated.MethodsTranscriptome profiling of intestinal mucosa biopsies were downloaded from the GEO database. Robust Rank Aggregation (RRA) analysis was performed to identify statistically changed genes and differentially expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. CIBERSORT was used to evaluate the proportion of 22 immune cells in biopsies. Weighted co-expression network analysis (WGCNA) was used to determine key module-related clinical traits. Protein-Protein Interaction (PPI) network and Cytoscape were performed to explore protein interaction network and screen hub genes. We used a validation cohort and colitis mouse model to validate hub genes. Several online websites were used to predict competing endogenous RNA (ceRNA) network.ResultsRRA integrated analysis revealed 1838 statistically changed genes from four training cohorts (adj. p-value < 0.05). GSEA showed that statistically changed genes were enriched in the innate immune system. CIBERSORT analysis uncovered an increase in activated dendritic cells (DCs) and M1 macrophages. The red module of WGCNA was considered the most critical module related to active UC. Based on the results of the PPI network and Cytoscape analyses, we identified six critical genes and transcription factor NF-κB. RT-PCR revealed that andrographolide (AGP) significantly inhibited the expression of hub genes. Finally, we identified XIST and three miRNAs (miR-9-5p, miR-129-5p, and miR-340-5p) as therapeutic targets.ConclusionsOur integrated analysis identified four hub genes (CXCL1, IL1B, MMP1, and MMP10) regulated by NF-κB. We further revealed that AGP decreased the expression of hub genes by inhibiting NF-κB activation. Lastly, we predicted the involvement of ceRNA network in the regulation of NF-κB expression. Collectively, our results provide valuable information in understanding the molecular mechanisms of active UC. Furthermore, we predict the use of AGP and small RNA combination for the treatment of UC.

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“…[ 3 ]. Immune dysregulation regulated by CD4 + T cells is believed to be a key player in the pathogenesis of IBD [ 4 , 5 ]. Growing evidence suggests that CD4 + T cells-associated cytokines, including interferon (IFN)- γ , interleukin (IL)-10, IL-17A, are involved in the development of IBD [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

MiRNA-374b-5p and miRNA-106a-5p are related to inflammatory bowel disease via regulating IL-10 and STAT3 signaling pathways

Liu

et al. 2022

BMC Gastroenterol

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Background Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is one of the most frequent gastrointestinal disorders worldwide. Although the actual etiology of IBD remains unclear, growing evidence suggests that CD4+ T cells-associated cytokines, including interferon (IFN)-γ, interleukin (IL)-10 and IL-17A, are crucial for the occurrence of IBD. It has been reported that there is a positive association between miRNAs and IBD development. In this study, we investigated the roles of hsa-miRNA-374b-5p(miRNA-374b-5p) and hsa-miRNA-106a-5p(miRNA-106a-5p) in regulating IBD development. Methods Serum was obtained from vein blood of IBD patients and healthy controls, qRT-PCR was performed to study the expression of miRNA-374b-5p and miRNA-106a-5p. Furthermore, we investigate the effects of overexpression or inhibition of miRNA-374b-5p on naïve CD4 + T cell subsets differentiation from vein blood of healthy controls by RT-qPCR, flow cytometry and western blot. And more the prediction and confirmation of the targeting genes of miRNA-374b-5p and miRNA-106a-5p were performed by bioinformatics softwares and dual-luciferase reporter assay. Results The results showed that miRNA-106a-5p and miRNA-374b-5p were significantly overexpressed in IBD patients. MiRNA-374b-5p could enhance Th1/Th17 cell differentiation and was related to IBD pathogenesis. MiRNA-374b-5p overexpression induced the mRNA expression of IL-17A and IFN-γ, and suppressed that of IL-10 in T cells. MiRNA-374b-5p inhibition decreased the mRNA expression of IL-17A and IFN-γ, while upregulated that of IL-10 in T cells. These qPCR data were further verified at protein level by western blotting and flow cytometry. In addition, dual-luciferase reporter (DLR) assay indicated that miRNA-374b-5p was directly targeted by IL-10, a key anti-inflammatory cytokine for preventing the occurrence of IBD. Meanwhile, STAT3 was identified as a target gene of miRNA-106a-5p by DLR assays. Further analysis revealed that miRNA-374b-5p regulated JAK1 and STAT3 pathways in CD4+ T cells via IL-10/STAT3 axis. MiRNA-374b-5p overexpression remarkably decreased the mRNA expression and phosphorylated (ser-727) protein levels of STAT3, while miRNA-374b-5p inhibition had the opposite effects. Conclusion MiRNA-374b-5p and miRNA-106a-5p may contribute to IBD development by regulating IL-10/STAT3 signal transduction.

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Targeting of the Tec Kinase ITK Drives Resolution of T Cell–Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis

Cited by 13 publications

References 60 publications

Identification of molecular subtypes of ischaemic stroke based on immune‐related genes and weighted co‐expression network analysis

Identification of molecular subtypes of ischaemic stroke based on immune‐related genes and weighted co‐expression network analysis

Identification of Immune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis

MiRNA-374b-5p and miRNA-106a-5p are related to inflammatory bowel disease via regulating IL-10 and STAT3 signaling pathways

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