Immune cells in cardiac repair and regeneration

Abstract

The immune system is fundamental to tissue homeostasis and is the first line of defense following infection, injury or disease. In the damaged heart, large numbers of immune cells are recruited to the site of injury. These cells play an integral part in both repair by scar formation and the initiation of tissue regeneration. They initially assume inflammatory phenotypes, releasing pro-inflammatory cytokines and removing dead and dying tissue, before entering a reparative stage, replacing dead muscle tissue with a non-contractile scar. In this Review, we present an overview of the innate and adaptive immune response to heart injury. We explore the kinetics of immune cell mobilization following cardiac injury and how the different innate and adaptive immune cells interact with one another and with the damaged tissue. We draw on key findings from regenerative models, providing insight into how to support a robust immune response permissible for cardiac regeneration. Finally, we consider how the latest technological developments can offer opportunities for a deeper and unbiased functional understanding of the immune response to heart disease, highlighting the importance of such knowledge as the basis for promoting regeneration following cardiac injury in human patients.

Keywords: Cardiac; Immune system; Muscle; Regeneration.

Fig. 1.

Immune response to myocardial infarction. (A) Before injury, CCR2⁻ resident macrophages, mast cells and dendritic cells reside in the heart. (B) Following injury, an orchestrated cellular and molecular cascade takes place in the damaged heart, including the release of damage-associated molecular patterns (DAMPs) from dying cardiomyocytes and resident macrophages, and mast cell degranulation. (C) This activity triggers an inflammatory phase during which infiltrating innate immune cells (such as neutrophils and CCR2⁺ Ly6C^high monocytes) are recruited to the site to clear debris. (D) Pro-inflammatory CCR2⁺ Ly6C^high monocyte-derived macrophages phagocytose neutrophils to resolve inflammation, leading to an increase in production of anti-inflammatory and pro-fibrotic cytokines (e.g. IL10 and TGFβ) and subsequent downregulation of pro-inflammatory cytokines (e.g. IL1β and TNFα). CCR2⁺ Ly6C^high monocyte-derived macrophages then differentiate in situ into reparative CCR2⁺ Ly6C^low macrophages, via a nuclear receptor subfamily 4 group A member 1 (NR4A1)-dependent transcriptional program and, consequently, inflammation is superseded by a reparative stage. CCR2⁺ Ly6C^low monocyte-derived macrophages promote deposition of a fibrotic scar by directly secreting collagen and by inducing myofibroblast formation. (E) The newly formed collagen scar is permanent in adult mammals, leading to fibrotic repair of the heart. (F) However, in regenerative organisms the scar formed is transient in nature, being totally replaced by new cardiac muscle tissue.

Fig. 2.

Immune cell-cell interactions within the damaged heart are crucial for limiting scarring during heart repair. A key feature in the transition from an inflammatory response to permanent fibrosis or regeneration is the crosstalk between the many different immune cell types that populate the heart. Upon cardiac injury, paracrine signaling occurring between resident cardiac cells (e.g. cardiomyocytes, CCR2⁻ macrophages and mast cells) and infiltrating populations (e.g. neutrophils and CCR2⁺ monocytes and macrophages) determines the kinetics of immune responses and ultimately cardiac output and function following injury. Recruited neutrophils contribute to their own clearance, and therefore resolution of inflammation, by expressing NGAL, a marker that promotes the phagocytic capacity of monocyte-derived CCR2⁺ Ly6C^high pro-inflammatory macrophages. Upon ingestion of apoptotic neutrophils, CCR2⁺ Ly6C^high monocyte-derived macrophages increase production of anti-inflammatory and pro-fibrotic cytokines (e.g. IL10 and TGFβ) and subsequently downregulate expression of pro-inflammatory cytokines (e.g. IL1β and TNFα). This signaling cascade promotes in situ differentiation into CCR2⁺ Ly6C^low macrophages and contributes to resolution of tissue inflammation. Phagocytosing macrophages also decrease IL23 expression, which reduces IL17A production by γδ T cells. Whereas γδ T cells and neutrophils release IL17A within the damaged myocardium to increase neutrophil production and recruitment to the injured heart, decreased IL17A expression reduces neutrophil accumulation, which dampens inflammation and improves tissue healing overall. CCR2⁺ Ly6C^low pro-reparative macrophages contribute to tissue repair by directly depositing collagen into the fibrotic scar and by activating collagen-depositing myofibroblasts via TGFβ. This pro-fibrotic repair is promoted by CD4⁺ and CD8⁺ T cells through an IFNγ-dependent pathway, but counterbalanced by eosinophil and NK cell inhibition of collagen overproduction by myofibroblasts. Please see main text for further details.