Communication in the heart: the role of the innate immune system in coordinating cellular responses to ischemic injury

Abstract

Ischemic cardiac injury is the leading cause of heart failure and mortality in the USA and is a major expense to health-care systems. Once the heart is injured, a highly dynamic and coordinated immune response is initiated, which is dependent on both resident and recruited leukocytes. The goal of the inflammatory response is to remove ischemic and necrotic material and to promote infarct healing. If this system is perturbed, the myocardium heals poorly, leading to significant left ventricular dysfunction. Understanding how inflammatory cells coordinate and interact with each other is required prior to designing therapeutic interventions that target pathological processes at play and leave untouched those processes that are protective. This review will discuss the intercellular cross talk between cells of the innate immune system following myocardial ischemic injury and how that response is coordinated over time.

Figure 1

Recruitment dynamics of monocytes following ischemia-reperfusion injury. C57Bl/6 male mice (6–10 weeks) were instrumented via small thoracotomy by placing a suture under the left anterior descending artery. The suture ends were exteriorized through the chest wall and the skin was closed. Animals recovered (7 days) and were then subject to 90 min ischemia using this closed-chest model of ischemia-reperfusion injury [66]. After 1 (D1) and 6 (D6) days, mice were sacrificed, infarcted tissue was minced and digested (collagenase I and VI, hyaluronidase, DNase) for 60 min at 37°C and filtered to produce a single cell suspension that was subject to flow cytometric analysis ¹. Cells were initially gated on CD45⁺ cells (not shown). Monocytes were identified as CD45⁺CD11b⁺LIN⁻(LIN=CD90,B220,NK1.1,CD92, CD49b,Ly-6G)⁻,(CD11c,I-A^b,F4/80)^Int and either Ly-6c^Hi or Ly-6c^Low. M/DC were identified as CD45⁺CD11b⁺LIN⁻(CD11c, I-A^b, F4/80)^Hi Ly-6c^Low. Neutrophils were CD45⁺CD11b⁺LIN⁺ (CD11c,I-A^b, F4/80)^LowLy-6c^Int

Figure 2

Intercellular coordination of the innate immune response to acute cardiac injury. Shortly after I/R injury (A), resident cardiac mast cells rapidly degranulate and release pro-inflammatory cytokines and molecules that activate the endothelium, increase vascular permeability and activate resident monocytes and macrophages. There is an initial recruitment of Ly-6c^Hi monocytes, which potentiates the massive recruitment of neutrophils. After transendothelial migration, neutrophils follow a multiple chemotactic cues (ATP, chemokines and stimulation through formyl peptide receptors), to reach the site of injury. During this process, neutrophils secrete numerous degradative enzymes that allow them to ultimately reach cardiomyocytes. Neutrophils bind cardiomyocytes through an IL-6 dependent fashion, which triggers an intense oxidative burst, and subsequent cardiomyocyte injury death. As the immune response evolves over time (B), there is a large influx of Ly-6c^Hi monocytes produced in the spleen that occur in an AngII dependent fashion. Recruitment of Ly-6c^Hi monocytes is also promoted by multiple chemokines (including MCP-1) and apoptotic neutrophils. Ly-6c^Hi monocytes phagocytose apoptotic neutrophils and secrete anti-inflammatory cytokines such as IL-10, TGF-β and NO, which limit the inflammatory response. In addition, decreased monocyte/macrophage production of IL-23, which blunts IL-17a production from γδ T cells and other regulator T cells, decreases cardiomyocyte death and neutrophil generation in the bone marrow.