Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

Abstract

The importance of the immune system for cardiac repair following myocardial infarction is undeniable; however, the complex nature of immune cell behavior has limited the ability to develop effective therapeutics. This limitation highlights the need for a better understanding of the function of each immune cell population during the inflammatory and resolution phases of cardiac repair. The development of reliable therapies is further complicated by aging, which is associated with a decline in cell and organ function and the onset of cardiovascular and immunological diseases. Aging of the immune system has important consequences on heart function as both chronic cardiac inflammation and an impaired immune response to cardiac injury are observed in older individuals. Several studies have suggested that rejuvenating the aged immune system may be a valid therapeutic candidate to prevent or treat heart disease. Here, we review the basic patterns of immune cell behavior after myocardial infarction and discuss the autonomous and nonautonomous manners of hematopoietic stem cell and immune cell aging. Lastly, we identify prospective therapies that may rejuvenate the aged immune system to improve heart function such as anti-inflammatory and senolytic therapies, bone marrow transplant, niche remodeling and regulation of immune cell differentiation.

Keywords: aging; immune system; inflammation; myocardial infarction; therapeutics.

Figure 1

Typical immune cell and tissue responses in the heart after permanent coronary artery occlusion. (A) The generalized pattern of immune cell infiltration to the heart after ischemic injury. Here, immune cell infiltrate is subdivided into myeloid and lymphoid populations. Myeloid cell infiltration spans approximately 1–3 days post-MI, while lymphoid cell populations infiltrate the heart at approximately 3–7 days post-MI. (B) Systemic tissue response to MI. After MI, signals from the heart (e.g., from degranulating mast cells, dying cardiomyocytes or activated fibroblasts) act on the spleen and bone marrow to initiate tissue repair. The activation of HSCs and migration of immune cells is triggered by a diverse array of molecules, including but not limited to CCL2, CXCL12 (SDF-1), GM-CSF and IL-1β. Monocytopoiesis is regulated by IL-1β and CCL-2. Gradually, HSCs in the bone marrow will repopulate the spleen in part through chemotactic molecules such as KITL (SCF).

Figure 2

Mechanisms and consequences of immune cell aging. Cell intrinsic (autonomous) mechanisms of immune cell aging include mutations, epigenetic anomalies and metabolic reprogramming. Cell extrinsic factors that influence immune cell aging include deterioration of the bone marrow niche and co-morbidities, such as coronary artery disease or diabetes. With time, HSCs encounter various autonomous and non-autonomous drivers of aging that have downstream consequences on cell phenotype and systemic tissue function. Aged HSCs undergo enhanced myelopoiesis (myeloid skewing), mobilization to the circulation and self-renewal and show deficiencies in lymphopoiesis, BM homing and their ability to respond appropriately to tissue damage.

Figure 3

Putative rejuvenation therapies to reverse HSC and immune cell aging.