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.
Original language | English (US) |
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Article number | e87315 |
Journal | JCI Insight |
Volume | 1 |
Issue number | 12 |
DOIs | |
State | Published - Aug 4 2016 |
Funding
This work was supported by NIH grants 1P01AI116501, R01 HL113931, R01 HL094601, K08 HL123519, K08 HL 125940, and AG050096; Veteran’s Administration Merit Review grant 1I01BX002730; Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CHII2015-462); Foundation of Barnes-Jewish Hospital (8038-88); and a Burroughs Foundation Welcome Fund. We thank Eric T. Olson for assistance with graphic design for Figure 8. We thank Mark Miller and The In Vivo Imaging Core, Washington University, for assistance with 2 photon imaging, and we thank Scott Worthen, University of Pennsylvania, and Klaus Ley, La Jolla Institute for Allergy and Immunology, for originally providing CXCL5-deficient and LysM-GFP mice, respectively, to Mark Miller.
ASJC Scopus subject areas
- General Medicine