Embryonic Macrophages in Cardiac Development (p 1498)
Leid et al examine the contribution of embryonic macrophages to heart development.
While most monocyte-derived macrophages originate from hematopoietic precursors in the bone marrow, embryonic macrophages originate from tissues of the embryo and fetus, such as the primitive yolk sac and liver. During development, these macrophages enter tissues and organs where, in some cases, they remain throughout life. Despite their embryonic origin, it is unclear whether they play a role in organ development. To find out, Leid and colleagues first catalogued embryonic macrophages in the developing mouse heart. They found that macrophages initially appear at embryonic stage E12.5 and that these early settlers differed from those arriving later (E14.5) both in their expression of cell surface receptor CCR2 (being CCR2− and CCR2+, respectively) and in their origin. Lineage tracing experiments revealed that the early CCR2− cells arose from the yolk sac, while the later CCR2+ cells came from fetal progenitors. Using transgenic mice the team went on to show that while CCR2+ cells were largely dispensable for normal heart development, CCR2− cells were essential for correct patterning of the coronary microvasculature. Investigating whether CCR2− cells might also contribute to adult coronary angio- and arteriogenesis could be of future clinical interest.
Hcy Induces Caspase-1 Dependent Pyroptosis (p 1525)
Xi et al show that high levels of homocystein can kill vascular endothelial cells by two different routes.
Hyperhomocysteinemia (HHcy), characterized by high circulating levels of homocysteine (Hcy) is a robust risk factor for cardiovascular disease. HHcy is associated with increased vascular endothelial cell damage, which leads to inflammation and, in turn, atherogenesis. Nevertheless, the mehanisms by which Hcy causes endothelial damage are unclear. Xi and colleagues now show that Hcy, but not its homologue, cysteine (used as a control), leads to the death of cultured human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. While the majority of the cell death induced by Hcy was apoptotic in nature, some was also due to pyroptosis—a recently identified form of apoptosis, which involves the formation of an inflammasome complex prior to the activation of caspases characteristic of programmed cell death. Pyroptosis is generally triggered in response to infection, but in this instance, it was induced by Hcy, a sterile metabolic stress stimulus. Future investigations into how Hcy instigates both pyroptosis and apoptosis in endothelial cells could provide new insights into how to prevent vascular damage in HHcy patients.
CCR5Teff Cells Drive Atherosclerosis (p 1540)
Li et al characterize a major T cell subset residing in atherosclerotic plaques.
After monocytes and macrophages, T cells are the next largest population of immune cells present in atherosclerotic plaques, but what drives the recruitment of these cells and what are their defining features? In searching for the answers to these questions, Li and colleagues have discovered that around half the T cells present in plaques express the cell surface marker CCR5—a chemokine receptor involved in T cell recruitment. They also showed that this receptor and its ligand were critical for homing of the cells to aortas in vitro and in vivo. The investigators went on to show that these CCR5+, plaque-residing T cells express an unexpected combination of T-bet—a transcription factor expressed by proinflammatory T effector cells (Teffs)—and FoxP3—a transcription factor expressed by anti-inflammatory T regulatory cells (Tregs). Despite the expression of FoxP3, however, the CCR5 cells were unable to suppress Teff proliferation (a feature of Tregs), shared an expression profile similar to that of Teffs, and were proatherogenic in adoptive transfer experiments: the cells increased plaque formation in atherosclerosis-prone mice. Collectively, these findings identify a new type of effector T cells that, at least in mice, contribute to atherosclerosis.
- © 2016 American Heart Association, Inc.