Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β
Hsi-Min Hsiao, … , Ankit Bharat, Daniel Kreisel
Hsi-Min Hsiao, … , Ankit Bharat, Daniel Kreisel
Published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2833-2847. https://doi.org/10.1172/JCI98436.
View: Text | PDF
Research Article

Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β

  • Text
  • PDF
Abstract

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-1β 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.

Authors

Hsi-Min Hsiao, Ramiro Fernandez, Satona Tanaka, Wenjun Li, Jessica H. Spahn, Stephen Chiu, Mahzad Akbarpour, Daniel Ruiz-Perez, Qiang Wu, Cem Turam, Davide Scozzi, Tsuyoshi Takahashi, Hannah P. Luehmann, Varun Puri, G.R. Scott Budinger, Alexander S. Krupnick, Alexander V. Misharin, Kory J. Lavine, Yongjian Liu, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel

×

Figure 5

IL-1β production by graft-infiltrating monocytes is essential for neutrophil extravasation after lung transplantation.

Options: View larger image (or click on image) Download as PowerPoint
IL-1β production by graft-infiltrating monocytes is essential for neutro...
(A) Recipient monocytes (CD45.2+CD11b+Ly6Chi) were isolated from the bone marrow or lung grafts in resting mice or 2 hours after transplantation of B6 CD45.1+ lungs into B6 CD45.2+ recipients, and their expression levels of Il1b, Tnfa, Cxcl1, Cxcl2, and Cxcl5 were analyzed by quantitative PCR. n = 4 each compartment with 1 statistical outlier for Cxcl1 and 1 statistical outlier for Cxcl5 in the lung excluded from analysis. *P < 0.05, Mann-Whitney U test. (B) Expression levels of IL1B in human donor grafts at conclusion of cold ischemia and 2 hours after reperfusion, assessed by quantitative PCR. n = 5. **P < 0.01, paired t test. (C) Arterial blood oxygenation was assessed and absolute numbers of recipient (D) monocytes and (E) neutrophils were determined in lung grafts 24 hours after transplantation of B6 CD45.1+ lungs into splenectomized congenic B6 CD45.2+ recipients that received either B6 WT or B6 IL-1β–deficient monocytes. Data are expressed as median with interquartile range. n = 6 per group. **P < 0.01, Mann-Whitney U test. (F) Representative contour plots of extravascular vs. intravascular neutrophils and quantification of the percentage of graft-infiltrating neutrophils in lung grafts and (G) number of neutrophils in BALF 24 hours after transplantation of B6 CD45.1+ lungs into splenectomized B6 CD45.2+ recipients that received B6 WT or B6 IL-1β–deficient monocytes. Data are expressed as median with interquartile range. n = 6 per group. *P < 0.05; **P < 0.01, Mann-Whitney U test. (H) Representative intravital 2-photon microscopy of B6 WT or B6 IL-1R–KO lung grafts 2 hours after transplantation into syngeneic B6 LysM-GFP mice and quantification of neutrophil extravasation. Qdot 655 labeled the vessels red. Recipient neutrophils are green. Scale bar: 50 μm. Data are expressed as median with interquartile range. n = 4 per group. *P < 0.05, Mann-Whitney U test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts