The innate immune system after ischemic injury: lessons to be learned from the heart and brain

Abstract

Innate immune cells are critically involved in ischemic complications of atherosclerosis. While new insight emerged on the origin and role of leukocytes in steady state, the knowledge about myeloid cells' sources, functions, and fate after stroke is limited. In our review, we highlight open questions in this important area while examining potential parallels in the immune response after stroke and myocardial infarction. We stress the need to better understand systemic interactions between ischemic tissue, immunity, and hematopoiesis, as turnover of leukocytes in inflammatory sites can be rapid, and cell production and supply may serve as future therapeutic targets to modulate inflammation in the vessel wall, brain, and heart.

Figure 1. Putative organ networks after myocardial infarction and stroke

The cartoon illustrates events after ischemic injury of either the brain or the heart that lead to accelerated disease progression in atherosclerotic plaque (some events are experimentally proven in mice, others are still hypothetical). The enlarged inset depicts processes in the bone marrow microenvironment after MI. Here, niche cells provide signals that regulate hematopoietic stem cell activity, retention and leukocyte production. After MI, increased sympathetic nervous signaling releases noradrenaline in the bone marrow niche, which binds to β₃ adrenoreceptors on niche cells. These withdraw the soluble factor SDF-1 which results in increased hematopoietic progenitor cell activity and emigration to extramedullary sites. Similar processes may be active after stroke. Increased production of leukocytes then feeds an expanded pool of circulating monocytes which are recruited to the injured brain or myocardial infarct, but also to atherosclerotic plaque in higher numbers, accelerating plaque growth and vulnerability. This feedback loop may cause the high clinical reoccurrence rates of MI and stroke. HSC: hematopoietic stem cell. HSPC: hematopoietic stem and progenitor cells. CAR: CXCL12 abundant reticular cell, Mϕ: macrophage.