Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation

• Published in: Cell reports (Cambridge) 2022-05, Vol.39 (8), p.110847-110847, Article 110847
• Main Authors: Westhaver, Lauren P., Nersesian, Sarah, Nelson, Adam, MacLean, Leah K., Carter, Emily B., Rowter, Derek, Wang, Jun, Gala-Lopez, Boris L., Stadnyk, Andrew W., Johnston, Brent, Boudreau, Jeanette E.
• Format: Article
• Language: English
• Subjects: arginase; arginine metabolism; damage-associated molecular patterns (DAMPs); immunoregulation; lymphocytes; mass spectrometry; mitochondria; natural killer cell; NK cell; tissue damage
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110847

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. [Display omitted] •Activation of NK and T cells is overridden in the presence of mitochondrial DAMPs•Arginase liberated from mitochondria drives the NK and T cell regulatory program•mitoDAMP signals to NK and T cells may prevent excessive inflammation/autoimmunity Westhaver et al. demonstrate that damage-associated molecular patterns released from the mitochondria during cell death induce a dominant and rapid regulatory program in natural killer and T cells. Arginase, released from the mitochondria, and the resultant depletion of environmental arginine are central in this switch of lymphocyte function.