Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury.

Abstract

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.

• Authors: Daniel R Calabrese, Emily Aminian, Benat Mallavia, Fengchun Liu, Simon J Cleary, Oscar A Aguilar, Ping Wang, Jonathan P Singer, Steven R Hays, Jeffrey A Golden, Jasleen Kukreja, Daniel Dugger, Mary Nakamura, Lewis L Lanier, Mark R Looney, John R Greenland
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 3 (02 01 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 33290276 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Klrk1 protein, mouse
• NK Cell Lectin-Like Receptor Subfamily K

Topics

• Animals
• Humans
• Killer Cells, Natural (immunology, pathology)
• Lung (immunology, pathology)
• Lung Diseases (immunology, pathology)
• Lymphocyte Activation
• Mice
• Mice, Knockout
• NK Cell Lectin-Like Receptor Subfamily K (immunology)
• Reperfusion Injury (immunology, pathology)