Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 7, Pages 2833-2847Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI98436
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Funding
- NIH [1P01AI116501, R01 HL094601, P01 AG049665, P01 HL071643, HL125940, R01 HL125655, R01 HL131908]
- Veterans Administration Merit Review [1I01BX002730]
- Foundation for Barnes-Jewish Hospital
- NIH Transplant Scientist Training Program [T32 DK077662]
- International Society of Heart and Lung Transplantation Research awards
- Department of the Army [W81XWH-15-1-0215]
- Thoracic Surgery Foundation
- American Lung Association
- Society of University Surgeons
- Cancer Center support grant [NCI CA060553]
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lschemia-reperfusion injury, a form of sterile inflammation, is the leading risk factor for both short-term mortality following pulmonary transplantation and chronic lung allograft dysfunction. While it is well recognized that neutrophils are critical mediators of acute lung injury, processes that guide their entry into pulmonary tissue are not well understood. Here, we found that CCR2(+) classical monocytes are necessary and sufficient for mediating extravasation of neutrophils into pulmonary tissue during ischemia-reperfusion injury following hilar clamping or lung transplantation. The classical monocytes were mobilized from the host spleen, and splenectomy attenuated the recruitment of classical monocytes as well as the entry of neutrophils into injured lung tissue, which was associated with improved graft function. Neutrophil extravasation was mediated by MyD88-dependent IL-1 beta production by graft-infiltrating classical monocytes, which downregulated the expression of the tight junction-associated protein ZO-2 in pulmonary vascular endothelial cells. Thus, we have uncovered a crucial role for classical monocytes, mobilized from the spleen, in mediating neutrophil extravasation, with potential implications for targeting of recipient classical monocytes to ameliorate pulmonary ischemia-reperfusion injury in the clinic.
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