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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.
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Research Article Transplantation

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

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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

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Figure 2

Classical monocytes mediating neutrophil extravasation in lungs subjected to IRI through hilar clamping are mobilized from the spleen.

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Classical monocytes mediating neutrophil extravasation in lungs subjecte...
Numbers of classical monocytes in the (A) lung, (B) spleen, and (C) bone marrow before and 2 hours after hilar clamp–mediated lung IRI. Numbers of classical monocytes in the lung and spleen are shown after treatment with isotype control or anti-CCR2 antibody. (D) Numbers of classical monocytes in bone marrow of resting mice after treatment with isotype control or anti-CCR2 antibody. Data are expressed as median with interquartile range. n = 5 per group. *P < 0.05, Mann-Whitney U test. (E) Recruitment of classical monocytes to injured lung and (F) percentage of extravasated neutrophils in injured lung after hilar clamp–mediated IRI in the presence or absence of a spleen. Congenic spleen transplants were performed into hosts that had undergone native splenectomies. Splenectomy of the transplanted spleen (resplenectomy) rendered these mice asplenic. txp, transplant. For E, 1 statistical outlier in the spleen transplant and 1 statistical outlier in resplenectomy group were excluded from the analysis. For F, 1 statistical outlier was excluded in the splenectomy group. Data are expressed as mean ± SEM. n = 6–8 per group. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 1-way ANOVA with post hoc Holm-Šídák test (A–C, E, F).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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