iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction
The role of proinflammation, and specifically TNF-α, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-α, we reveal increased macrophages (MΦs) that were skewed towards a more proinflammatory (M1) state a...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2018
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| _version_ | 1797095410492243968 |
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| author | Barnette, D Cahill, T Gunadasa-Rohling, M Carr, C Freeman, M Riley, P |
| author_facet | Barnette, D Cahill, T Gunadasa-Rohling, M Carr, C Freeman, M Riley, P |
| author_sort | Barnette, D |
| collection | OXFORD |
| description | The role of proinflammation, and specifically TNF-α, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-α, we reveal increased macrophages (MΦs) that were skewed towards a more proinflammatory (M1) state at day 4, followed by more reparative, antiinflammatory (M2) state at day 7 after myocardial infarction (MI). However, associated functional cytokine expression was significantly reduced in iRhom2-mutant M1 and M2 MΦs, respectively. A dampened proinflammatory signature in iRhom2-deficient mice during the acute phase of injury and subsequent changes in MΦ polarization were associated with reduced phagocytosis and a more sparse distribution within the scar region. This resulted in impaired collagen deposition and fibrosis, and increased left ventricular remodelling and mortality in iRhom2-deficient mice after MI. Our findings reveal a requirement for an iRhom2-mediated proinflammatory response during downstream scarring and fibrosis, which is driven in part by TNF-α signaling. These conclusions challenge the existing model that infarct repair is determined exclusively by antiinflammatory signaling of M2 MΦs, and as such we propose an alternative view of immunomodulation to maintain effective healing after infarction. |
| first_indexed | 2024-03-07T04:27:27Z |
| format | Journal article |
| id | oxford-uuid:cd233363-b43c-454a-96a4-c7a4ac917f46 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:27:27Z |
| publishDate | 2018 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:cd233363-b43c-454a-96a4-c7a4ac917f462022-03-27T07:26:42ZiRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarctionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cd233363-b43c-454a-96a4-c7a4ac917f46EnglishSymplectic Elements at OxfordAmerican Society for Clinical Investigation2018Barnette, DCahill, TGunadasa-Rohling, MCarr, CFreeman, MRiley, PThe role of proinflammation, and specifically TNF-α, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-α, we reveal increased macrophages (MΦs) that were skewed towards a more proinflammatory (M1) state at day 4, followed by more reparative, antiinflammatory (M2) state at day 7 after myocardial infarction (MI). However, associated functional cytokine expression was significantly reduced in iRhom2-mutant M1 and M2 MΦs, respectively. A dampened proinflammatory signature in iRhom2-deficient mice during the acute phase of injury and subsequent changes in MΦ polarization were associated with reduced phagocytosis and a more sparse distribution within the scar region. This resulted in impaired collagen deposition and fibrosis, and increased left ventricular remodelling and mortality in iRhom2-deficient mice after MI. Our findings reveal a requirement for an iRhom2-mediated proinflammatory response during downstream scarring and fibrosis, which is driven in part by TNF-α signaling. These conclusions challenge the existing model that infarct repair is determined exclusively by antiinflammatory signaling of M2 MΦs, and as such we propose an alternative view of immunomodulation to maintain effective healing after infarction. |
| spellingShingle | Barnette, D Cahill, T Gunadasa-Rohling, M Carr, C Freeman, M Riley, P iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| title | iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| title_full | iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| title_fullStr | iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| title_full_unstemmed | iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| title_short | iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| title_sort | irhom2 mediated proinflammatory signalling regulates heart repair following myocardial infarction |
| work_keys_str_mv | AT barnetted irhom2mediatedproinflammatorysignallingregulatesheartrepairfollowingmyocardialinfarction AT cahillt irhom2mediatedproinflammatorysignallingregulatesheartrepairfollowingmyocardialinfarction AT gunadasarohlingm irhom2mediatedproinflammatorysignallingregulatesheartrepairfollowingmyocardialinfarction AT carrc irhom2mediatedproinflammatorysignallingregulatesheartrepairfollowingmyocardialinfarction AT freemanm irhom2mediatedproinflammatorysignallingregulatesheartrepairfollowingmyocardialinfarction AT rileyp irhom2mediatedproinflammatorysignallingregulatesheartrepairfollowingmyocardialinfarction |