Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling
Wenjun Li ... Kory J. Lavine, Daniel Kreisel
Wenjun Li ... Kory J. Lavine, Daniel Kreisel
Published August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e87315. doi:10.1172/jci.insight.87315.
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Categories: Research Article Inflammation Transplantation

Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling

Abstract

It is well established that maladaptive innate immune responses to sterile tissue injury represent a fundamental mechanism of disease pathogenesis. In the context of cardiac ischemia reperfusion injury, neutrophils enter inflamed heart tissue, where they play an important role in potentiating tissue damage and contributing to contractile dysfunction. The precise mechanisms that govern how neutrophils are recruited to and enter the injured heart are incompletely understood. Using a model of cardiac transplant–mediated ischemia reperfusion injury and intravital 2-photon imaging of beating mouse hearts, we determined that tissue-resident CCR2+ monocyte–derived macrophages are essential mediators of neutrophil recruitment into ischemic myocardial tissue. Our studies revealed that neutrophil extravasation is mediated by a TLR9/MyD88/CXCL5 pathway. Intravital 2-photon imaging demonstrated that CXCL2 and CXCL5 play critical and nonredundant roles in guiding neutrophil adhesion and crawling, respectively. Together, these findings uncover a specific role for a tissue-resident monocyte-derived macrophage subset in sterile tissue inflammation and support the evolving concept that macrophage ontogeny is an important determinant of function. Furthermore, our results provide the framework for targeting of cell-specific signaling pathways in myocardial ischemia reperfusion injury.

Authors

Wenjun Li, Hsi-Min Hsiao, Ryuji Higashikubo, Brian T. Saunders, Ankit Bharat, Daniel R. Goldstein, Alexander S. Krupnick, Andrew E. Gelman, Kory J. Lavine, Daniel Kreisel

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Intravital 2-photon imaging reveals impaired neutrophil trafficking in h...

Figure 1

Intravital 2-photon imaging reveals impaired neutrophil trafficking in heart grafts that lack monocyte-derived macrophages.

(A) Control PBS liposome–treated heart graft with neutrophil (green) arrest inside blood vessels (blood vessels appear red after injection of quantum dots), intravascular cluster formation, and extravasation (see Supplemental Video 1; n = 4 mice). Neutrophil trafficking in hearts derived from (B) donors that received treatment with clodronate liposomes prior to organ harvest (see Supplemental Video 2; n = 4 mice). Relative time is displayed in hrs:min:sec. Scale bars: 50 μm. (C) Percentage of neutrophils that extravasated during imaging period was significantly higher in hearts derived from control PBS liposome–treated donors compared with heart grafts harvested from clodronate liposome–treated mice. (D) Neutrophil rolling velocities were comparable in coronary veins of cardiac grafts derived from control PBS liposome–treated and clodronate liposome–treated mice. (E) Intraluminal crawling velocities were significantly lower in hearts harvested from clodronate liposome–treated WT compared with PBS liposome–treated mice. *P < 0.05; **P < 0.01 (t test). Data in C, D, and E are derived from 4 mice for each experimental group. For D and E, symbols represent averages obtained from individual mice with over 30 neutrophils examined per mouse, horizontal bars denote means, and error bars denote ±SEM.