دورية أكاديمية

Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo.

التفاصيل البيبلوغرافية
العنوان: Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo.
المؤلفون: Jacob N; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 10945 Le Conte Ave., Suite 2114, Los Angeles, CA, 90095, USA. njacob@mednet.ucla.edu.; Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA. njacob@mednet.ucla.edu., Kumagai K; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Abraham JP; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Shimodaira Y; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Ye Y; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Luu J; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Blackwood AY; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Castanon SL; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Stamps DT; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Thomas LS; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Gonsky R; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Shih DQ; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Michelsen KS; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA., Targan SR; F. Widjaja Foundation, Cedars-Sinai Medical Center, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA, 90048, USA.
المصدر: Scientific reports [Sci Rep] 2020 Oct 23; Vol. 10 (1), pp. 18189. Date of Electronic Publication: 2020 Oct 23.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Signal Transduction*, Intestinal Diseases/*metabolism , Receptors, Tumor Necrosis Factor, Member 25/*metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15/*metabolism, Animals ; Fibroblasts/metabolism ; Fibrosis/metabolism ; Mice ; Mice, Transgenic ; Receptors, Tumor Necrosis Factor, Member 25/genetics ; Tumor Necrosis Factor Ligand Superfamily Member 15/genetics
مستخلص: Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag -/- , Rag -/- mice lacking DR3 in all cell types (Rag -/- Dr3 -/- ), or Rag -/- mice lacking DR3 only on fibroblasts (Rag -/- Dr3 ∆Col1a2 ) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag -/- mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag -/- Dr3 -/- demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag -/- , Rag -/- Dr3 ∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.
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معلومات مُعتمدة: T32 DK007180 United States DK NIDDK NIH HHS; T32 DK07180-40 United States NH NIH HHS; P01 DK046763 United States DK NIDDK NIH HHS; K08 DK093578 United States DK NIDDK NIH HHS; R01 DK056328-16 United States NH NIH HHS; R01 DK056328 United States DK NIDDK NIH HHS
المشرفين على المادة: 0 (Receptors, Tumor Necrosis Factor, Member 25)
0 (Tnfrsf25 protein, mouse)
0 (Tnfsf15 protein, mouse)
0 (Tumor Necrosis Factor Ligand Superfamily Member 15)
تواريخ الأحداث: Date Created: 20201024 Date Completed: 20210510 Latest Revision: 20231216
رمز التحديث: 20231216
مُعرف محوري في PubMed: PMC7584589
DOI: 10.1038/s41598-020-75168-5
PMID: 33097818
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-020-75168-5