Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype.
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 CD163(high) human leukocyte antigen-DR(low) 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.
Boyle
Joseph J
JJ
Vascular Sciences Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K. joseph.boyle@imperial.ac.uk
Harrington
Heather A
HA
Piper
Emma
E
Elderfield
Kay
K
Stark
Jaroslav
J
Landis
Robert C
RC
Haskard
Dorian O
DO
D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D050197:Atherosclerosis / Q000235:genetics* / Q000517:prevention & control*; D001344:Autopsy; D023921:Coronary Stenosis / Q000150:complications / Q000473:pathology*; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000473:pathology*; D018613:Microscopy, Confocal; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000032:analysis; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface