Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction

Zhikun Zheng, Stephen Chiu, Mahzad Akbarpour, Haiying Sun, Paul A. Reyfman, Kishore R. Anekalla, Hiam Abdala-Valencia, Daphne Edgren, Wenjun Li, Daniel Kreisel, Farida V. Korobova, Ramiro Fernandez, Alexandra Mcquattie-Pimentel, Zheng J. Zhang, Harris Perlman, Alexander V. Misharin, G. R.Scott Budinger, Ankit Bharat

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19 Scopus citations

Abstract

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.

Original languageEnglish
Article number4508
JournalScience translational medicine
Volume9
Issue number394
DOIs
StatePublished - Jun 14 2017

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    Zheng, Z., Chiu, S., Akbarpour, M., Sun, H., Reyfman, P. A., Anekalla, K. R., Abdala-Valencia, H., Edgren, D., Li, W., Kreisel, D., Korobova, F. V., Fernandez, R., Mcquattie-Pimentel, A., Zhang, Z. J., Perlman, H., Misharin, A. V., Budinger, G. R. S., & Bharat, A. (2017). Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Science translational medicine, 9(394), [4508]. https://doi.org/10.1126/scitranslmed.aal4508