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Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype

Boyle, J.J., Harrington, H.A., Elderfield, K., Stark, J., #Landis, R.C., Haskard, D.O.

Clive Landis

American Journal of Pathology





Macrophage biology


Intraplaque hemorrhage accelerates atherosclerosis via oxidant stress and contributes to lesion development and destabilization. Normally, macrophages scavenge hemoglobin-haptoglobin (HbHp) complexes via CD163, and this process provokes the secretion of the anti-inflammatory atheroprotective cytokine interleukin (IL)-10. We therefore tested the hypothesis that HbHp complexes may drive monocyte differentiation to an atheroprotective phenotype. Examination of the macrophage phenotype in hemorrhaged atherosclerotic plaques revealed a novel hemorrhage-associated macrophage population (HA-mac), defined by high levels of CD163, but low levels of human leukocyte antigen-DR. HA-mac contained more iron, a pro-oxidant catalyst, but paradoxically had less oxidative injury, measured by 8-oxo-guanosine content. Differentiating monocytes with HbHp complexes reproduced the CD163high human leukocyte antigen-DRlow HA-mac phenotype in vitro. These in vitro HA-mac cells cleared Hb more quickly, and consistently showed less hydrogen peroxide release, highly reactive oxygen species and oxidant stress, and increased survival. Differentiation to HA-mac was prevented by neutralizing IL-10 antibodies, indicating that IL-10 mediates an autocrine feedback mechanism in this system. Nonlinear dynamic modeling showed that an IL-10/CD163-positive feedback loop drove a discrete HA-mac lineage. Simulations further indicated an all-or-none switch to HA-mac at threshold levels of HbHp, and this conversion was experimentally verified. These data demonstrate the creation of a novel atheroprotective (HA-mac) macrophage subpopulation in response to intraplaque hemorrhage and raise the possibility that therapeutically reproducing this macrophage phenotype may be cardio-protective in cases of atherosclerosis.


American Society for Investigative Pathology


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