Editors' ChoiceAtherosclerosis

The trash piles up in vascular disease

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Science Translational Medicine  03 Aug 2016:
Vol. 8, Issue 350, pp. 350ec124
DOI: 10.1126/scitranslmed.aah4511

As cells divide and choose their fates during development, many of them undergo programmed death to meet the needs of the developing organism. Professional phagocytic cells of the innate immune system engulf these dead cells to clear away the debris, making room for new healthy ones. This balance between death and the clearance of dead cells, or efferocytosis, is critical for maintaining tissue homeostasis. In an attempt to understand why dead cells accumulate in atherosclerotic lesions and put plaques at risk for rupture, Kojima et al. made an unexpected discovery that cells in the vessel wall block their own clearance by instructing phagocytes to ignore them.

The “don’t-eat-me” signal CD47 instructs phagocytes to ignore healthy cells, and the loss of CD47 leads to the rapid clearance of erythrocytes, platelets, and other immune cells. The authors found that vascular and immune cells up-regulate the expression of CD47, which impairs clearance of dying and dead cell debris from the developing plaque and propagates lesion expansion. In several mouse models of atherosclerosis, antibodies that block CD47 reduced lesion area, demonstrating that efferocytosis can be rescued by turning off the “don’t-eat-me” signals. Although the concept of impaired efferocytosis in the atherosclerotic plaque is not new, this study is the first to demonstrate that this defect also occurs in the dying cells, which are actively sending signals to prevent their own clearance. Perhaps this begins as a survival mechanism to preserve nonimmune cells from clearance, but in the setting of chronic inflammation this process contributes to disease.

These findings provide a strong rationale for therapeutically targeting efferocytosis in atherosclerosis. Targeting CD47 using biologics is currently being explored to treat malignancies where the elevated expression of CD47 is predictive of poor survival, such as leukemia. Given the parallel mechanisms used in the vessel wall, there is potential to specifically harness the power of anti-CD47 treatment as a new avenue to treat the complications of atherosclerotic vascular disease.

Y. Kojima et al., CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 10.1038/nature18935 (2016). [Abstract]

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