TY - JOUR
T1 - Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction
AU - Zheng, Zhikun
AU - Chiu, Stephen
AU - Akbarpour, Mahzad
AU - Sun, Haiying
AU - Reyfman, Paul A.
AU - Anekalla, Kishore R.
AU - Abdala-Valencia, Hiam
AU - Edgren, Daphne
AU - Li, Wenjun
AU - Kreisel, Daniel
AU - Korobova, Farida V.
AU - Fernandez, Ramiro
AU - Mcquattie-Pimentel, Alexandra
AU - Zhang, Zheng J.
AU - Perlman, Harris
AU - Misharin, Alexander V.
AU - Budinger, G. R.Scott
AU - Bharat, Ankit
N1 - Funding Information:
We thank S. Swaminathan for assistance with multicolor flow cytometry, C. Arvanitis for technical assistance with multiphoton imaging, and E. Susan for administrative assistance and for formatting the manuscript. Funding: This study was supported by NIH T32DK077662 and American Society for Transplant Surgery (to S.C.); NIH P01AG049665, NIH P01HL071643, and Department of Defense PR141319 (to G.R.S.B., H.P., and A.V.M.); and NIH HL125940, Thoracic Surgery Foundation, American Lung Association, and Society of University Surgeons (to A.B.). The Northwestern University Flow Cytometry Core Facility is supported by National Cancer Institute (NCI) Cancer Center Support Grant (CCSG) (NCICA060553). Flow cytometry cell sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01. Imaging work performed at the Northwestern University Center for Advanced Microscopy was generously supported by NCI CCSGP30CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope, acquired through the support of NIH 1S10OD010398-01.
PY - 2017/6/14
Y1 - 2017/6/14
N2 - Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia-reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that donor-derived intravascular nonclassical monocytes (NCMs) are retained in human and murine donor lungs used in transplantation and can be visualized at sites of endothelial injury after reperfusion. When NCMs in the donor lungs were depleted, either pharmacologically or genetically, neutrophil influx and lung graft injury were attenuated in both allogeneic and syngeneic models. Similar protection was observed when the patrolling function of donor NCMs was impaired by deletion of the fractalkine receptor CX3CR1. Unbiased transcriptomic profiling revealed up-regulation of MyD88 pathway genes and a key neutrophil chemoattractant, CXCL2, in donor-derived NCMs after reperfusion. Reconstitution of NCM-depleted donor lungs with wild-type but not MyD88- deficient NCMs rescued neutrophil migration. Donor NCMs, through MyD88 signaling, were responsible for CXCL2 production in the allograft and neutralization of CXCL2 attenuated neutrophil influx. These findings suggest that therapies to deplete or inhibit NCMs in donor lung might ameliorate primary graft dysfunction with minimal toxicity to the recipient.
AB - Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia-reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that donor-derived intravascular nonclassical monocytes (NCMs) are retained in human and murine donor lungs used in transplantation and can be visualized at sites of endothelial injury after reperfusion. When NCMs in the donor lungs were depleted, either pharmacologically or genetically, neutrophil influx and lung graft injury were attenuated in both allogeneic and syngeneic models. Similar protection was observed when the patrolling function of donor NCMs was impaired by deletion of the fractalkine receptor CX3CR1. Unbiased transcriptomic profiling revealed up-regulation of MyD88 pathway genes and a key neutrophil chemoattractant, CXCL2, in donor-derived NCMs after reperfusion. Reconstitution of NCM-depleted donor lungs with wild-type but not MyD88- deficient NCMs rescued neutrophil migration. Donor NCMs, through MyD88 signaling, were responsible for CXCL2 production in the allograft and neutralization of CXCL2 attenuated neutrophil influx. These findings suggest that therapies to deplete or inhibit NCMs in donor lung might ameliorate primary graft dysfunction with minimal toxicity to the recipient.
UR - http://www.scopus.com/inward/record.url?scp=85020903592&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aal4508
DO - 10.1126/scitranslmed.aal4508
M3 - Article
C2 - 28615357
AN - SCOPUS:85020903592
SN - 1946-6234
VL - 9
JO - Science translational medicine
JF - Science translational medicine
IS - 394
M1 - 4508
ER -