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FC2 Activating transcription factor 1 co-regulates iron, lipid and anti-inflammatory target genes to direct a novel atheroprotective human plaque macrophage subset
  1. J J Boyle1,
  2. M Johns1,
  3. A T Nguyen1,
  4. J Yu1,
  5. L Game2,
  6. D J Schaer2,
  7. J C Mason1,
  8. D O Haskard1
  1. 1NHLI Cardiovascular Sciences, Imperial College London, UK
  2. 2MRC Clinical Sciences Centre, Imperial College London, UK


Rationale Monocytes entering tissues, including advanced atherosclerotic plaques, rapidly mature and adapt to their new microenvironment. Intraplaque haemorrhage promotes human atherosclerosis progression and destabilisation via a dual metabolic challenge: cholesterol-enriched erythrocyte membranes and haem-iron. In human coronary culprit lesions, we recently described a novel macrophage subset (M-haem) with atheroprotective properties (IL-10high HO1high CD163high HLADRlow MPOlow 8keto-Guanosinelow).

Methodology We dissected the mechanism of M-haem differentiation by microarray, computational biology and gene manipulation in human primary macrophages and human coronary lesions.

Results Microarray analysis showed that M-haem cells were distinct from conventional M1 or M2 subsets. Using computational biology, we identified a simple transcriptional network motif with activating transcription factor 1 (ATF1) as a hub co-inducing HO1, SOCS1 and NR1H2 (LXR-α). Silencing RNA experiments showed that ATF1 induction was required for haem to upregulate HO-1 SOCS1 and NR1H2. Luciferase analysis confirmed that ATF1 transcriptionally activated both HO-1 and LXR. Luciferase deletion mutants indicated that the key ATF1-site in the HO-1 enhancer was distal (−2.2 kb to −4.9 kb). Binding experiments showed that ATF1 bound to this sequence. ATF1 overexpression in human macrophages conferred the characteristics of M-haem cells, including co-induction of HO-1, NR1H2, resistance to foam cell formation, increased survival and antioxidant protection.

Conclusions Our data define the molecular basis of the differentiation of M-haem, a novel atheroprotective macrophage subset. Our data indicate that redirection of macrophage phenotype in atherosclerosis progression is a modality appropriate for therapeutic development.

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