TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary
Background & Aims: Crohn’s disease (CD) is a debilitating inflammatory disorder that affects more than 1.6 million people in North America alone. Members of the tumor necrosis factor superfamily are key regulators of intestinal inflammation; specifically, tumor necrosis factor–like weak inducer...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
|
| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X19300712 |
| _version_ | 1818061731328425984 |
|---|---|
| author | Luca Di Martino Abdullah Osme Sarah Kossak-Gupta Theresa T. Pizarro Fabio Cominelli |
| author_facet | Luca Di Martino Abdullah Osme Sarah Kossak-Gupta Theresa T. Pizarro Fabio Cominelli |
| author_sort | Luca Di Martino |
| collection | DOAJ |
| description | Background & Aims: Crohn’s disease (CD) is a debilitating inflammatory disorder that affects more than 1.6 million people in North America alone. Members of the tumor necrosis factor superfamily are key regulators of intestinal inflammation; specifically, tumor necrosis factor–like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor–inducible 14 (Fn14), are involved in normal and pathologic tissue remodeling. Our aim was to determine the role of TWEAK/Fn14 in CD and a murine model of CD-like ileitis (ie, SAMP1/YitFc [SAMP] strain). Methods: SAMP mice deficient in Fn14 (SAMP × Fn14-/-) were developed and a detailed time-course study was performed evaluating ileal tissues by histology and stereomicroscopy, as well as quantitative polymerase chain reaction and NanoString technology (Seattle, WA). Reciprocal bone marrow chimeras were generated to assess the relevance of Fn14 in hematopoietic vs nonhematopoietic compartments. Surgically resected intestinal tissues and mucosal biopsy specimens from patients with CD, ulcerative colitis, and healthy controls were analyzed for the expression of TWEAK/Fn14 by quantitative polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. Results: SAMP × Fn14-/- showed a marked decrease in ileitis severity at 20 weeks of age compared with SAMP WT controls. Bone marrow chimeras showed that Fn14 was required in both hematopoietic and nonhematopoietic compartments for ileitis to develop. Transcriptome data showed multiple cellular pathways regulated by Fn14 signaling. Finally, increased expression of TWEAK and Fn14 was observed in tissue lesions from CD patients compared with ulcerative colitis and healthy controls. Conclusions: TWEAK/Fn14 are up-regulated in CD, and also mediate experimental CD-like ileitis, by regulation of multiple innate and adaptive cellular pathways. Therefore, TWEAK/Fn14 may represent a novel therapeutic target for the treatment of small intestinal inflammation in CD. Keywords: Gut Immunity, Intestinal Inflammation, Gene Expression, Proinflammatory Cytokines |
| first_indexed | 2024-12-10T13:52:58Z |
| format | Article |
| id | doaj.art-262d14705fee4fe4ba0278c4a248235f |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-10T13:52:58Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-262d14705fee4fe4ba0278c4a248235f2022-12-22T01:46:06ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2019-01-0183427446TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummaryLuca Di Martino0Abdullah Osme1Sarah Kossak-Gupta2Theresa T. Pizarro3Fabio Cominelli4Division of Gastroenterology and Liver Disease, Case Western University School of Medicine, Cleveland, Ohio; Department of Medicine, Case Western University School of Medicine, Cleveland, OhioDivision of Gastroenterology and Liver Disease, Case Western University School of Medicine, Cleveland, Ohio; Department of Medicine, Case Western University School of Medicine, Cleveland, OhioDivision of Gastroenterology and Liver Disease, Case Western University School of Medicine, Cleveland, Ohio; Department of Medicine, Case Western University School of Medicine, Cleveland, OhioDivision of Gastroenterology and Liver Disease, Case Western University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western University School of Medicine, Cleveland, OhioDivision of Gastroenterology and Liver Disease, Case Western University School of Medicine, Cleveland, Ohio; Department of Medicine, Case Western University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western University School of Medicine, Cleveland, Ohio; Correspondence Address correspondence to: Fabio Cominelli, MD, PhD, Division of Gastroenterology and Liver Disease, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106. fax: (216) 368-0647.Background & Aims: Crohn’s disease (CD) is a debilitating inflammatory disorder that affects more than 1.6 million people in North America alone. Members of the tumor necrosis factor superfamily are key regulators of intestinal inflammation; specifically, tumor necrosis factor–like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor–inducible 14 (Fn14), are involved in normal and pathologic tissue remodeling. Our aim was to determine the role of TWEAK/Fn14 in CD and a murine model of CD-like ileitis (ie, SAMP1/YitFc [SAMP] strain). Methods: SAMP mice deficient in Fn14 (SAMP × Fn14-/-) were developed and a detailed time-course study was performed evaluating ileal tissues by histology and stereomicroscopy, as well as quantitative polymerase chain reaction and NanoString technology (Seattle, WA). Reciprocal bone marrow chimeras were generated to assess the relevance of Fn14 in hematopoietic vs nonhematopoietic compartments. Surgically resected intestinal tissues and mucosal biopsy specimens from patients with CD, ulcerative colitis, and healthy controls were analyzed for the expression of TWEAK/Fn14 by quantitative polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. Results: SAMP × Fn14-/- showed a marked decrease in ileitis severity at 20 weeks of age compared with SAMP WT controls. Bone marrow chimeras showed that Fn14 was required in both hematopoietic and nonhematopoietic compartments for ileitis to develop. Transcriptome data showed multiple cellular pathways regulated by Fn14 signaling. Finally, increased expression of TWEAK and Fn14 was observed in tissue lesions from CD patients compared with ulcerative colitis and healthy controls. Conclusions: TWEAK/Fn14 are up-regulated in CD, and also mediate experimental CD-like ileitis, by regulation of multiple innate and adaptive cellular pathways. Therefore, TWEAK/Fn14 may represent a novel therapeutic target for the treatment of small intestinal inflammation in CD. Keywords: Gut Immunity, Intestinal Inflammation, Gene Expression, Proinflammatory Cytokineshttp://www.sciencedirect.com/science/article/pii/S2352345X19300712 |
| spellingShingle | Luca Di Martino Abdullah Osme Sarah Kossak-Gupta Theresa T. Pizarro Fabio Cominelli TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary Cellular and Molecular Gastroenterology and Hepatology |
| title | TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary |
| title_full | TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary |
| title_fullStr | TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary |
| title_full_unstemmed | TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary |
| title_short | TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune PathwaysSummary |
| title_sort | tweak fn14 is overexpressed in crohn s disease and mediates experimental ileitis by regulating critical innate and adaptive immune pathwayssummary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X19300712 |
| work_keys_str_mv | AT lucadimartino tweakfn14isoverexpressedincrohnsdiseaseandmediatesexperimentalileitisbyregulatingcriticalinnateandadaptiveimmunepathwayssummary AT abdullahosme tweakfn14isoverexpressedincrohnsdiseaseandmediatesexperimentalileitisbyregulatingcriticalinnateandadaptiveimmunepathwayssummary AT sarahkossakgupta tweakfn14isoverexpressedincrohnsdiseaseandmediatesexperimentalileitisbyregulatingcriticalinnateandadaptiveimmunepathwayssummary AT theresatpizarro tweakfn14isoverexpressedincrohnsdiseaseandmediatesexperimentalileitisbyregulatingcriticalinnateandadaptiveimmunepathwayssummary AT fabiocominelli tweakfn14isoverexpressedincrohnsdiseaseandmediatesexperimentalileitisbyregulatingcriticalinnateandadaptiveimmunepathwayssummary |