Inflammation in cardiac injury, repair and regeneration

Abstract

Purpose of review: Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. This manuscript discusses new findings that advanced our understanding of the role of inflammation in cardiac injury and repair.

Recent findings: Recently published studies have identified interleukin-1α and RNA released by necrotic cardiomyocytes as key danger signals that trigger the inflammatory response following infarction. Interleukin-1 promotes activation of a proinflammatory phenotype in leukocytes and fibroblasts, and delays myofibroblast transdifferentiation. Inhibitory lymphocytes play a crucial role in negative regulation of the postinfarction inflammatory response by modulating macrophage and fibroblast phenotype. Cardiac macrophages exhibit significant heterogeneity and phenotypic plasticity and may orchestrate the reparative response following infarction. In neonatal mice, resident embryonic macrophage subpopulations may promote a regenerative response. In contrast, in adult animals replacement of resident macrophage populations with monocyte-derived macrophages may induce inflammation while inhibiting cardiac regeneration. These exciting observations highlight the crucial role of macrophages in cardiac injury and repair, but should be interpreted with caution considering the limitations of murine models of neonatal myocardial injury.

Summary: Design of novel strategies to reduce cardiac injury, improve repair and promote regeneration is dependent on understanding of the cell biology of the inflammatory response.

Figure 1

Release of damage-associated molecular patterns (DAMPs) in the infarcted myocardium initiates the inflammatory response and may extend injury. High mobility group box-1 (HMGB-1), extracellular RNA (eRNA), heat shock proteins (HSP) and Interleukin (IL)-1α are released by necrotic cardiomyocytes (CM) and activate innate immune signaling pathways in leukocytes (N, neutrophil; Ma, macrophage), endothelial cells (EC) and fibroblasts (F).

Figure 2

T cell subsets, such as regulatory T cells (Tregs) invariant Natural killer T cells (iNKT) are recruited in the infarct through CC chemokine-dependent pathways and may be important cellular effectors in negative regulation of the post-infarction inflammatory response. Lymphocyte subpopulations may modulate macrophage (Ma), endothelial cell (EC), and fibroblast phenotype by secreting soluble mediators (such as IL-10 and TGF-β), or through contact-dependent interactions (Mo, monocyte).