TY - JOUR
T1 - Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1ß
AU - Hsiao, Hsi Min
AU - Fernandez, Ramiro
AU - Tanaka, Satona
AU - Li, Wenjun
AU - Spahn, Jessica H.
AU - Chiu, Stephen
AU - Akbarpour, Mahzad
AU - Ruiz-Perez, Daniel
AU - Wu, Qiang
AU - Turam, Cem
AU - Scozzi, Davide
AU - Takahashi, Tsuyoshi
AU - Luehmann, Hannah P.
AU - Puri, Varun
AU - Budinger, G. R.Scott
AU - Krupnick, Alexander S.
AU - Misharin, Alexander V.
AU - Lavine, Kory J.
AU - Liu, Yongjian
AU - Gelman, Andrew E.
AU - Bharat, Ankit
AU - Kreisel, Daniel
N1 - Funding Information:
This work was supported by NIH 1P01AI116501 and R01 HL094601 (to DK and AEG), Veterans Administration Merit Review 1I01BX002730, the Foundation for Barnes-Jewish Hospital (to DK and AEG), the NIH Transplant Scientist Training Program (T32 DK077662 to RF and SC), International Society of Heart and Lung Transplantation Research awards (to HMH and RF), NIH P01 AG049665, NIH P01 HL071643, Department of the Army W81XWH-15-1-0215 (to GRSB and AVM), and NIH HL125940, the Thoracic Surgery Foundation, the American Lung Association, and the Society of University Surgeons (to AB). The Northwestern University Flow Cytometry Core Facility is supported by a Cancer Center support grant (NCI CA060553). Flow cytometry cell sorting at Northwestern University was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01. YL and HPL were supported by NIH R01 HL125655 and NIH R01 HL131908. We thank the Molecular Microbiology Imaging Facility at Washington University in St. Louis for their technical support.
Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/7/2
Y1 - 2018/7/2
N2 - Ischemia-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-1ß 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.
AB - Ischemia-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-1ß 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.
UR - http://www.scopus.com/inward/record.url?scp=85049855195&partnerID=8YFLogxK
U2 - 10.1172/JCI98436
DO - 10.1172/JCI98436
M3 - Article
C2 - 29781811
AN - SCOPUS:85049855195
SN - 0021-9738
VL - 128
SP - 2833
EP - 2847
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -