PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia.
OBJECTIVE
Migration of monocytes into the arterial wall contributes to arterial inflammation and atherosclerosis progression. Since elevated low-density lipoprotein cholesterol (LDL-C) levels have been associated with activation of plasma monocytes, intensive LDL-C lowering may reverse these pro-inflammatory changes. Using proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) which selectively reduce LDL-C, we studied the impact of LDL-C lowering on monocyte phenotype and function in patients with familial hypercholesterolaemia (FH) not using statins due to statin-associated muscle symptoms.


RESULTS
We assessed monocyte phenotype and function using flow cytometry and a trans-endothelial migration assay in FH patients (n = 22: LDL 6.8 ± 1.9 mmol/L) and healthy controls (n = 18, LDL 2.9 ± 0.8 mmol/L). Monocyte chemokine receptor (CCR) 2 expression was approximaterly three-fold higher in FH patients compared with controls. C-C chemokine receptor type 2 (CCR2) expression correlated significantly with plasma LDL-C levels (r = 0.709) and was positively associated with intracellular lipid accumulation. Monocytes from FH patients also displayed enhanced migratory capacity ex vivo. After 24 weeks of PCSK9 mAb treatment (n = 17), plasma LDL-C was reduced by 49%, which coincided with reduced intracellular lipid accumulation and reduced CCR2 expression. Functional relevance was substantiated by the reversal of enhanced migratory capacity of monocytes following PCSK9 mAb therapy.


CONCLUSIONS
Monocytes of FH patients have a pro-inflammatory phenotype, which is dampened by LDL-C lowering by PCSK9 mAb therapy. LDL-C lowering was paralleled by reduced intracellular lipid accumulation, suggesting that LDL-C lowering itself is associated with anti-inflammatory effects on circulating monocytes.
Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Sophie J
SJ
Bernelot Moens
Experimental Vascular Biology, Medical Biochemistry, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Annette E
AE
Neele
Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Jeffrey
J
Kroon
Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Fleur M
FM
van der Valk
Experimental Vascular Biology, Medical Biochemistry, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Jan
J
Van den Bossche
Experimental Vascular Biology, Medical Biochemistry, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Marten A
MA
Hoeksema
Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Renate M
RM
Hoogeveen
Experimental Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Johan G
JG
Schnitzler
Sanofi, Clinical Development, R&D, 371 Rue du Professeur Blayac, 34080, Montpellier, France.
Marie T
MT
Baccara-Dinet
Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA.
Garen
G
Manvelian
Experimental Vascular Biology, Medical Biochemistry, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Institute for Cardiovascular Prevention (IPEK), Pettenkoferstraße 8a & 9, 80336 Munich, Germany.
Menno P J
MPJ
de Winther
Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Erik S G
ESG
Stroes
D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000071449:Proprotein Convertase 9 / Q000276:immunology*; D054390:Receptors, CCR2 / Q000187:drug effects / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C515334:CCR2 protein, human; D008078:Cholesterol, LDL; D054390:Receptors, CCR2; D048069:Tumor Necrosis Factors; D016753:Interleukin-10; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C577155:evolocumab; C571059:alirocumab
Atherosclerosis ; CCR2; Hypercholesterolaemia; Inflammation ; PCSK9 