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

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

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 6

MyD88 expression by graft-infiltrating monocytes is essential for neutrophil extravasation after lung transplantation.

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MyD88 expression by graft-infiltrating monocytes is essential for neutro...
(A) Expression levels of IL-1β were assessed by quantitative real-time PCR in bone marrow–derived B6 WT or MyD88-deficient monocytes after treatment with B6 lung lysates. Data are expressed as mean ± SEM of 3 biological replicates. **P < 0.01, unpaired t test. (B) Arterial blood oxygenation was assessed and absolute numbers of recipient (C) monocytes and (D) 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 MyD88-deficient monocytes. (E) Representative contour plots of extravascular vs. intravascular neutrophils and quantification of the percentages of graft-infiltrated neutrophils in lung grafts as well as (F) number of neutrophils in BALF 24 hours after transplantation of B6 CD45.1+ lungs into splenectomized congenic B6 CD45.2+ recipients that received either B6 WT or B6 MyD88-deficient monocytes. Data are expressed as median with interquartile range. n = 5 per group. *P < 0.05; **P < 0.01, Mann-Whitey U test (B–F).