Li Wenjun, Hsiao Hsi-Min, Higashikubo Ryuji, Saunders Brian T, Bharat Ankit, Goldstein Daniel R, Krupnick Alexander S, Gelman Andrew E, Lavine Kory J, Kreisel Daniel
Department of Surgery and.
Department of Pathology and Immunology, Washington University of Medicine, St. Louis, Missouri, USA.
JCI Insight. 2016 Aug 4;1(12). doi: 10.1172/jci.insight.87315.
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.
众所周知，对无菌性组织损伤的适应性先天免疫反应是疾病发病机制的一种基本机制。在心脏缺血再灌注损伤的背景下，中性粒细胞进入发炎的心脏组织，在加重组织损伤和导致收缩功能障碍方面发挥重要作用。目前尚不完全清楚控制中性粒细胞如何被招募到受损心脏并进入其中的精确机制。利用心脏移植介导的缺血再灌注损伤模型和跳动小鼠心脏的活体双光子成像，我们确定组织驻留的CCR2单核细胞衍生巨噬细胞是中性粒细胞招募到缺血心肌组织中的关键介质。我们的研究表明，中性粒细胞外渗是由TLR9/MyD88/CXCL5途径介导的。活体双光子成像表明，CXCL2和CXCL5分别在引导中性粒细胞黏附和爬行中发挥关键且不可替代的作用。总之，这些发现揭示了组织驻留单核细胞衍生巨噬细胞亚群在无菌性组织炎症中的特定作用，并支持了巨噬细胞个体发生是功能重要决定因素这一不断发展的概念。此外，我们的结果为心肌缺血再灌注损伤中细胞特异性信号通路的靶向治疗提供了框架。
