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

HM Hsiao, R Fernandez, S Tanaka… - The Journal of …, 2018 - Am Soc Clin Investig
HM Hsiao, R Fernandez, S Tanaka, W Li, JH Spahn, S Chiu, M Akbarpour, D Ruiz-Perez…
The Journal of clinical investigation, 2018Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation