Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis
In human patients and animal models of ulcerative colitis (UC), upregulation of the mitochondrial translocator protein (TSPO) in the colon is consistent with inflammation. Although the molecular function for TSPO remains unclear, it has been investigated as a therapeutic target for ameliorating UC p...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.896951/full |
| _version_ | 1811284106381623296 |
|---|---|
| author | Isabel A. Jimenez Isabel A. Jimenez Allison P. Stilin Kanako Morohaku Kanako Morohaku Mahmoud H. Hussein Prasanthi P. Koganti Vimal Selvaraj |
| author_facet | Isabel A. Jimenez Isabel A. Jimenez Allison P. Stilin Kanako Morohaku Kanako Morohaku Mahmoud H. Hussein Prasanthi P. Koganti Vimal Selvaraj |
| author_sort | Isabel A. Jimenez |
| collection | DOAJ |
| description | In human patients and animal models of ulcerative colitis (UC), upregulation of the mitochondrial translocator protein (TSPO) in the colon is consistent with inflammation. Although the molecular function for TSPO remains unclear, it has been investigated as a therapeutic target for ameliorating UC pathology. In this study, we examined the susceptibility of Tspo gene-deleted (Tspo−/−) mice to insults as provided by the dextran sodium sulfate (DSS)-induced acute UC model. Our results show that UC clinical signs and pathology were severely exacerbated in Tspo−/− mice compared to control Tspofl/fl cohorts. Histopathology showed extensive inflammation and epithelial loss in Tspo−/− mice that caused an aggravated disease. Colonic gene expression in UC uncovered an etiology linked to precipitous loss of epithelial integrity and disproportionate mast cell activation assessed by tryptase levels in Tspo−/− colons. Evaluation of baseline homeostatic shifts in Tspo−/− colons revealed gene expression changes noted in elevated epithelial Cdx2, mast cell Cd36 and Mcp6, with general indicators of lower proliferation capacity and elevated mitochondrial fatty acid oxidation. These findings demonstrate that intact physiological TSPO function serves to limit inflammation in acute UC, and provide a systemic basis for investigating TSPO-targeting mechanistic therapeutics. |
| first_indexed | 2024-04-13T02:23:37Z |
| format | Article |
| id | doaj.art-2e6277f6eb394b3abc7b04709d7f718c |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-13T02:23:37Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-2e6277f6eb394b3abc7b04709d7f718c2022-12-22T03:06:50ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-08-011310.3389/fphys.2022.896951896951Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitisIsabel A. Jimenez0Isabel A. Jimenez1Allison P. Stilin2Kanako Morohaku3Kanako Morohaku4Mahmoud H. Hussein5Prasanthi P. Koganti6Vimal Selvaraj7Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, United StatesDepartment of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, United StatesDepartment of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, United StatesSchool of Science and Technology, Institute of Agriculture, Shinshu University, Nagano, JapanDepartment of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, United StatesDepartment of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, United StatesDepartment of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, United StatesIn human patients and animal models of ulcerative colitis (UC), upregulation of the mitochondrial translocator protein (TSPO) in the colon is consistent with inflammation. Although the molecular function for TSPO remains unclear, it has been investigated as a therapeutic target for ameliorating UC pathology. In this study, we examined the susceptibility of Tspo gene-deleted (Tspo−/−) mice to insults as provided by the dextran sodium sulfate (DSS)-induced acute UC model. Our results show that UC clinical signs and pathology were severely exacerbated in Tspo−/− mice compared to control Tspofl/fl cohorts. Histopathology showed extensive inflammation and epithelial loss in Tspo−/− mice that caused an aggravated disease. Colonic gene expression in UC uncovered an etiology linked to precipitous loss of epithelial integrity and disproportionate mast cell activation assessed by tryptase levels in Tspo−/− colons. Evaluation of baseline homeostatic shifts in Tspo−/− colons revealed gene expression changes noted in elevated epithelial Cdx2, mast cell Cd36 and Mcp6, with general indicators of lower proliferation capacity and elevated mitochondrial fatty acid oxidation. These findings demonstrate that intact physiological TSPO function serves to limit inflammation in acute UC, and provide a systemic basis for investigating TSPO-targeting mechanistic therapeutics.https://www.frontiersin.org/articles/10.3389/fphys.2022.896951/fullcoloninflammationmast cellmitochondriaintestinal epithelium |
| spellingShingle | Isabel A. Jimenez Isabel A. Jimenez Allison P. Stilin Kanako Morohaku Kanako Morohaku Mahmoud H. Hussein Prasanthi P. Koganti Vimal Selvaraj Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis Frontiers in Physiology colon inflammation mast cell mitochondria intestinal epithelium |
| title | Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis |
| title_full | Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis |
| title_fullStr | Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis |
| title_full_unstemmed | Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis |
| title_short | Mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis |
| title_sort | mitochondrial translocator protein deficiency exacerbates pathology in acute experimental ulcerative colitis |
| topic | colon inflammation mast cell mitochondria intestinal epithelium |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.896951/full |
| work_keys_str_mv | AT isabelajimenez mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT isabelajimenez mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT allisonpstilin mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT kanakomorohaku mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT kanakomorohaku mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT mahmoudhhussein mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT prasanthipkoganti mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis AT vimalselvaraj mitochondrialtranslocatorproteindeficiencyexacerbatespathologyinacuteexperimentalulcerativecolitis |