Anti-inflammatory changes in response to PCSK9 antibody treatment in monocytes of FH patients
PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemiaBernelot Moens SJ, Neele AE, Kroon J et al., - Eur Heart J (2017) 00, 1–10. doi:10.1093/eurheartj/ehx002
As the role of inflammation in atherogenesis cannot be explained by a causal role for C-reactive protein, focus has shifted towards immune cells [1,2]. Monocytes infiltrate atherosclerotic lesions  and monocyte-derived macrophages contribute to a local pro-inflammatory milieu in the plaque . The receptor for monocyte chemo-attractant protein 1 (MCP-1), C-C chemokine receptor type 2 (CCR2) plays an important role in the recruitment of monocytes to the arterial wall . Higher CCR2 expression is seen in patients with hypercholesterolaemia [6,7].
As opposed to statins, treatment with PCSK9 antibodies (mAbs) does not lead to a CRP reduction in addition to the LDL-c reduction . The effect of PCSK9 mAbs on other inflammatory mediators has not been reported on.
This study assessed the impact of elevated LDL-c levels on monocyte phenotype and function in patients with familial hypercholesterolaemia (FH, n=22), who are not receiving statins due to statin-associated muscle symptoms (SAMS), and compared this to matched normolipidaemic control subjects (n=18). The effect of 24 weeks PCSK9 mAbs (alirocumab: n=10, evolocumab: n=7) in FH patients on their monocytes was assessed, as compared with FH patients on stable statin treatment.
- Monocyte subset distribution did not differ significantly between FH patients and controls.
- CCR2 expression on classical monocytes of FH patients was increased, and expression levels correlated with plasma LDL-c levels in these patients (r=0.709, P=0.005).
- A 1.6-fold increase in monocyte migration was seen in monocytes of FH patients compared with controls.
- FH patients showed a higher fraction of lipid-positive monocytes (76±12% vs. 62±12%, P=0.02).
- Cells with high CCR2 expression also showed a higher number of lipid droplets, as compared to those with intermediate levels of CCR2.
- Treatment with PCSK9 mAbs did not affect CRP as compared with baseline, nor monocyte subset distribution.
- CCR2 surface expression diminished by 60% after mAbs treatment, comparable to levels observed in FH patients using statins. Transendothelial migration was significantly reduced after PCSK9 mAbs, to similar levels as seen in statin users. Intracellular lipid accumulation was also lower in monocytes of FH patients treated with PCSK9 mAbs, as compared to baseline.
- Cytokine production following LPS stimulation was altered in PCSK9 mAb-treated subjects, such that production of TNF was reduced, and levels of anti-inflammatory IL-10 was enhanced. Cytokine levels of monocytes of PCSK9 mAb-treated patients were comparable to those seen in patients on stable statin therapy.
Monocytes from FH patients not on statin therapy due to SAMS, show pro-inflammatory and migratory changes and an increase in cytoplasmic lipid droplets. The observations suggest a direct relation between intracellular lipid accumulation and inflammatory changes in monocytes. After 24-week treatment with a PCSK9 mAb anti-inflammatory changes were seen in monocyte migratory capacity, lipid content, and inflammatory responsiveness, towards a profile seen in FH patients on stable statin use. These changes were seen in the absence of a decrease in CRP levels.