Journal
CELL REPORTS
Volume 39, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.110847
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Funding
- Natural Sciences and Engineering Research Council of Canada
- Research Nova Scotia
- Nova Scotia Research Innovation Trust
- Canada Foundation for Innovation
- Dalhousie Faculty of Medicine Scholarship
- Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute
- Dalhousie Medical Research Foundation (DMRF)'s Crease Endowment for Cancer Research
- Craig's Cause Pancreatic Cancer Society
- Nova Scotia Graduate Scholarships
- Genomics in Medicine Scholarship
- Killam Memorial Predoctoral Scholarship
- President's Award - CIHR Vanier award
- Terry Fox Research Institute and Craig's Cause Pancreatic Society
- Canadian Blood Services' Blood4Research program
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Tissue damage results in the release of damage-associated molecular patterns, including mitoDAMPs, which can regulate inflammation through the lymphocyte response. NK cells and T cells adopt regulatory phenotypes and functions in response to mitoDAMPs, interrupting cytotoxicity, interferon gamma production, T cell proliferation, and anti-viral T cell activation.
Tissue damage leads to loss of cellular and mitochondrial membrane integrity and release of damage -associated molecular patterns, including those of mitochondrial origin (mitoDAMPs). Here, we describe the lymphocyte response to mitoDAMPs. Using primary cells from mice and human donors, we demonstrate that natural killer (NK) cells and T cells adopt regulatory phenotypes and functions in response to mitoDAMPs. NK cell-mediated cytotoxicity, interferon gamma (IFN-g) production, T cell proliferation, and in vivo anti-viral T cell activation are all interrupted in the presence of mitoDAMPs or mitoDAMP-rich irradiated cells in in vitro and in vivo assays. Mass spectrometry analysis of mitoDAMPs demonstrates that arginase and products of its enzymatic activity are prevalent in mitoDAMP preparations. Functional validation by arginase inhibition and/or arginine add-back shows that arginine depletion is responsible for the alteration in immunologic polarity. We conclude that lymphocyte responses to mitoDAMPs reflect a highly conserved mechanism that regulates inflammation in response to tissue injury.
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