NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.
| Title: | NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes. |
|---|---|
| Authors: | Calabrese DR; Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.; Department of Medicine, UCSF, San Francisco, California, USA.; Tsao T; Department of Medicine, UCSF, San Francisco, California, USA.; Magnen M; Department of Medicine, UCSF, San Francisco, California, USA.; Valet C; Department of Medicine, UCSF, San Francisco, California, USA.; Gao Y; Department of Medicine, UCSF, San Francisco, California, USA.; Mallavia B; Department of Medicine, UCSF, San Francisco, California, USA.; Tian JJ; Department of Medicine, UCSF, San Francisco, California, USA.; Aminian EA; Department of Medicine, UCSF, San Francisco, California, USA.; Wang KM; Department of Medicine, UCSF, San Francisco, California, USA.; Shemesh A; Department of Medicine, UCSF, San Francisco, California, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.; Punzalan EB; Department of Medicine, UCLA, Los Angeles, California, USA.; Sarma A; Department of Medicine, UCSF, San Francisco, California, USA.; Calfee CS; Department of Medicine, UCSF, San Francisco, California, USA.; Christenson SA; Department of Medicine, UCSF, San Francisco, California, USA.; Langelier CR; Department of Medicine, UCSF, San Francisco, California, USA.; Hays SR; Department of Medicine, UCSF, San Francisco, California, USA.; Golden JA; Department of Medicine, UCSF, San Francisco, California, USA.; Leard LE; Department of Medicine, UCSF, San Francisco, California, USA.; Kleinhenz ME; Department of Medicine, UCSF, San Francisco, California, USA.; Kolaitis NA; Department of Medicine, UCSF, San Francisco, California, USA.; Shah R; Department of Medicine, UCSF, San Francisco, California, USA.; Venado A; Department of Medicine, UCSF, San Francisco, California, USA.; Lanier LL; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.; Department of Microbiology and Immunology and.; Greenland JR; Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.; Department of Medicine, UCSF, San Francisco, California, USA.; Sayah DM; Department of Medicine, UCLA, Los Angeles, California, USA.; Ardehali A; Department of Medicine, UCLA, Los Angeles, California, USA.; Kukreja J; Department of Surgery, UCSF, San Francisco, California, USA.; Weigt SS; Department of Medicine, UCLA, Los Angeles, California, USA.; Belperio JA; Department of Medicine, UCLA, Los Angeles, California, USA.; Singer JP; Department of Medicine, UCSF, San Francisco, California, USA.; Looney MR; Department of Medicine, UCSF, San Francisco, California, USA. |
| Source: | JCI insight [JCI Insight] 2022 Dec 22; Vol. 7 (24). Date of Electronic Publication: 2022 Dec 22. |
| Publication Type: | Multicenter Study; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| MeSH Terms: | Primary Graft Dysfunction*/etiology ; Lung Transplantation*/adverse effects; Lung/metabolism ; Humans ; NK Cell Lectin-Like Receptor Subfamily K ; Tumor Necrosis Factor-alpha |
| Abstract: | Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD. |
| References: | Cell Rep Med. 2020 Jul 21;1(4):. (PMID: 32754722); Am J Respir Crit Care Med. 2020 Oct 1;202(7):1046-1048. (PMID: 32463294); Cell Mol Immunol. 2018 May;15(5):470-479. (PMID: 29400704); Am J Transplant. 2009 Feb;9(2):389-96. (PMID: 19120076); J Heart Lung Transplant. 2017 Oct;36(10):1097-1103. (PMID: 28942784); PLoS One. 2017 Jul 7;12(7):e0180831. (PMID: 28686681); Cancer Res. 2008 Jun 15;68(12):4746-53. (PMID: 18559521); Nature. 2009 Jan 29;457(7229):557-61. (PMID: 19136945); Am J Transplant. 2019 May;19(5):1464-1477. (PMID: 30582269); J Immunol. 2005 Feb 15;174(4):1922-31. (PMID: 15699119); Am J Respir Cell Mol Biol. 2020 Mar;62(3):364-372. (PMID: 31647878); Am J Respir Crit Care Med. 2015 Feb 15;191(4):455-63. (PMID: 25485813); JCI Insight. 2017 May 4;2(9):. (PMID: 28469087); Am J Respir Crit Care Med. 2012 Sep 15;186(6):546-52. (PMID: 22822025); J Heart Lung Transplant. 2018 Jul;37(7):895-902. (PMID: 29602706); BMC Bioinformatics. 2018 Nov 6;19(1):404. (PMID: 30400809); Nephrol Dial Transplant. 2011 Dec;26(12):3873-81. (PMID: 21555390); Nat Immunol. 2013 Apr;14(4):404-12. (PMID: 23396170); Am J Transplant. 2017 Sep;17(9):2338-2349. (PMID: 28251796); Thorax. 2019 Apr;74(4):397-404. (PMID: 30381399); J Heart Lung Transplant. 2017 Oct;36(10):1037-1046. (PMID: 28779893); Nat Methods. 2015 May;12(5):453-7. (PMID: 25822800); J Gen Virol. 1998 Nov;79 ( Pt 11):2593-601. (PMID: 9820134); Am J Respir Cell Mol Biol. 2020 Oct;63(4):490-501. (PMID: 32551854); J Immunol. 2012 Feb 15;188(4):1668-74. (PMID: 22231698); Eur Respir J. 2005 Nov;26(5):948-68. (PMID: 16264058); Chest. 2013 Aug;144(2):616-622. (PMID: 23429890); Am J Transplant. 2019 Apr;19(4):1011-1023. (PMID: 30378766); Clin Transpl. 2012;:237-46. (PMID: 23721028); Transplantation. 2019 Mar;103(3):493-501. (PMID: 30211828); J Leukoc Biol. 2017 Feb;101(2):471-480. (PMID: 27601626); J Thorac Cardiovasc Surg. 1993 Mar;105(3):492-501. (PMID: 8445927); Am J Transplant. 2014 Apr;14(4):831-40. (PMID: 24512389); Proc Natl Acad Sci U S A. 2007 May 1;104(18):7512-5. (PMID: 17463084); Am J Respir Crit Care Med. 2013 Feb 15;187(4):417-23. (PMID: 23239157); Science. 2004 Mar 5;303(5663):1532-5. (PMID: 15001782); Int J Mol Sci. 2017 Sep 16;18(9):. (PMID: 28926962); J Heart Lung Transplant. 2019 May;38(5):493-503. (PMID: 30962148); Am J Respir Crit Care Med. 2013 Mar 1;187(5):527-34. (PMID: 23306540); J Heart Lung Transplant. 2022 May;41(5):641-653. (PMID: 34924263); Am J Transplant. 2021 Feb;21(2):815-824. (PMID: 32794295); J Thromb Haemost. 2019 Feb;17(2):403-414. (PMID: 30456926); Am J Physiol Lung Cell Mol Physiol. 2017 Apr 1;312(4):L531-L541. (PMID: 28130262); Am J Respir Crit Care Med. 2020 Jan 1;201(1):63-72. (PMID: 31394048); Transplantation. 2020 Aug;104(8):1712-1719. (PMID: 32732851); Ann Am Thorac Soc. 2019 Jan;16(1):22-28. (PMID: 30230362); Immunology. 2009 Sep;128(1):7-15. (PMID: 19689731); JCI Insight. 2018 Feb 8;3(3):. (PMID: 29415887); Annu Rev Immunol. 2013;31:413-41. (PMID: 23298206); J Clin Invest. 2012 Jul;122(7):2661-71. (PMID: 22684106); J Heart Lung Transplant. 2014 Feb;33(2):127-33. (PMID: 24374027); J Exp Med. 2022 Nov 7;219(11):. (PMID: 36066491); Front Immunol. 2018 Mar 08;9:441. (PMID: 29568297); JCI Insight. 2019 Nov 14;4(22):. (PMID: 31613800); J Clin Invest. 2021 Feb 1;131(3):. (PMID: 33290276); Front Immunol. 2017 Nov 20;8:1583. (PMID: 29209320); Nat Immunol. 2008 May;9(5):503-10. (PMID: 18425107); Transplant Proc. 2006 Sep;38(7):2195-8. (PMID: 16980040); Front Immunol. 2021 Oct 07;12:704172. (PMID: 34691018); J Thorac Dis. 2017 Oct;9(10):4084-4097. (PMID: 29268419); Haematologica. 2011 Oct;96(10):1543-7. (PMID: 21712539); Clin Immunol. 2021 Sep;230:108827. (PMID: 34428741); Am J Transplant. 2017 Aug;17(8):2192-2199. (PMID: 28375571) |
| Grant Information: | R01 HL130324 United States HL NHLBI NIH HHS; R01 HL161048 United States HL NHLBI NIH HHS; R35 HL161241 United States HL NHLBI NIH HHS; I01 CX002011 United States CX CSRD VA; IK2 BX005301 United States BX BLRD VA |
| Contributed Indexing: | Keywords: Immunology; NK cells; Neutrophils; Organ transplantation; Pulmonology |
| Substance Nomenclature: | 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (Tumor Necrosis Factor-alpha) |
| Entry Date(s): | Date Created: 20221108 Date Completed: 20221223 Latest Revision: 20260305 |
| Update Code: | 20260305 |
| PubMed Central ID: | PMC9869973 |
| DOI: | 10.1172/jci.insight.164603 |
| PMID: | 36346670 |
| Database: | MEDLINE |
Multicenter Study; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural