Resumen
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-γ) 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.
| Idioma original | English |
|---|---|
| Número de artículo | 110847 |
| Publicación | Cell Reports |
| Volumen | 39 |
| N.º | 8 |
| DOI | |
| Estado | Published - may. 24 2022 |
Nota bibliográfica
Funding Information:This research was supported by the Natural Sciences and Engineering Research Council of Canada , Research Nova Scotia , the Nova Scotia Research Innovation Trust , and the Canada Foundation for Innovation . L.P.W. is supported by a Dalhousie Faculty of Medicine Scholarship . L.K.M., S.N., A.N., and E.B.C. are trainees in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Dalhousie Medical Research Foundation (DMRF)’s Crease Endowment for Cancer Research to E.B.C. and funds provided by Craig’s Cause Pancreatic Cancer Society to A.N. L.K.M., S.N., and E.B.C. are recipients of Nova Scotia Graduate Scholarships. L.K.M. is additionally supported by a Genomics in Medicine Scholarship . S.N. and L.K.M. are additionally supported by a Killam Memorial Predoctoral Scholarship and the President’s Award. S.N. is additionally funded by a CIHR Vanier award. A.N. is additionally funded by the Terry Fox Research Institute and Craig’s Cause Pancreatic Society . J.E.B. is the DMRF Cameron Cancer Scientist. We gratefully acknowledge the support of the Dalhousie Faculty of Medicine CORES program for flow cytometry, mass spectrometry, and animal care. We are grateful to Dr. Douglas Mahoney (University of Calgary) for providing the VSV-ΔM51 virus used in experiments and Dr. I.P. Alwayn for his assistance in initiating this project. We gratefully acknowledge the support of Canadian Blood Services’ Blood4Research program and the Dartmouth, Nova Scotia, processing facility for providing buffy coats for research. We are grateful to Designs that Cell for assistance with our graphical abstract and figure design. Dalhousie University is located in Mi’kma’ki, the ancestral and unceded territory of the Mi’kmaq.
Funding Information:
This research was supported by the Natural Sciences and Engineering Research Council of Canada, Research Nova Scotia, the Nova Scotia Research Innovation Trust, and the Canada Foundation for Innovation. L.P.W. is supported by a Dalhousie Faculty of Medicine Scholarship. L.K.M. S.N. A.N. and E.B.C. are trainees in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Dalhousie Medical Research Foundation (DMRF)’s Crease Endowment for Cancer Research to E.B.C. and funds provided by Craig's Cause Pancreatic Cancer Society to A.N. L.K.M. S.N. and E.B.C. are recipients of Nova Scotia Graduate Scholarships. L.K.M. is additionally supported by a Genomics in Medicine Scholarship. S.N. and L.K.M. are additionally supported by a Killam Memorial Predoctoral Scholarship and the President's Award. S.N. is additionally funded by a CIHR Vanier award. A.N. is additionally funded by the Terry Fox Research Institute and Craig's Cause Pancreatic Society. J.E.B. is the DMRF Cameron Cancer Scientist. We gratefully acknowledge the support of the Dalhousie Faculty of Medicine CORES program for flow cytometry, mass spectrometry, and animal care. We are grateful to Dr. Douglas Mahoney (University of Calgary) for providing the VSV-ΔM51 virus used in experiments and Dr. I.P. Alwayn for his assistance in initiating this project. We gratefully acknowledge the support of Canadian Blood Services’ Blood4Research program and the Dartmouth, Nova Scotia, processing facility for providing buffy coats for research. We are grateful to Designs that Cell for assistance with our graphical abstract and figure design. Dalhousie University is located in Mi'kma’ki, the ancestral and unceded territory of the Mi'kmaq. Conceptualization, L.P.W. S.N. B.L.G.-L. B.G. and J.E.B.; methodology, L.P.W. S.N. A.N. L.K.M. E.B.C. D.R. A.W.S. and J.E.B.; validation, L.P.W. S.N. L.K.M. E.B.C. and J.E.B.; formal analysis, L.P.W. S.N. L.K.M. E.B.C. and J.E.B.; investigation, L.P.W. S.N. A.N. L.K.M. E.B.C. and D.R.; resources, B.J. J.W. A.W.S. and D.R.; data curation, L.P.W. L.K.M. and S.N.; writing – original draft, L.P.W. S.N. L.K.M. and J.E.B.; writing – review & editing, L.P.W. S.N. A.N. L.K.M. E.B.C. J.W. D.R. B.L.G.-L. B.J. A.W.S. and J.E.B.; visualization, L.P.W. S.N. and J.E.B.; supervision; J.E.B.; project administration, L.P.W. S.N. and J.E.B.; funding acquisition, J.E.B. The authors declare no competing interests.
Publisher Copyright:
© 2022 The Authors
ASJC Scopus Subject Areas
- General Biochemistry,Genetics and Molecular Biology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't