TY - JOUR
T1 - Impact of cholesterol on proinflammatory monocyte production by the bone marrow
AU - Stiekema, Lotte C. A.
AU - Willemsen, Lisa
AU - Kaiser, Yannick
AU - Prange, Koen H. M.
AU - Wareham, Nicholas J.
AU - Boekholdt, S. Matthijs
AU - Kuijk, Carlijn
AU - de Winther, Menno P. J.
AU - Voermans, Carlijn
AU - Nahrendorf, Matthias
AU - Stroes, Erik S. G.
AU - Kroon, Jeffrey
N1 - Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2021/11/7
Y1 - 2021/11/7
N2 - Aim: Preclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects. Methods and results: A multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (β = 0.131 [95% CI: 0.036-0.225]; P = 0.007), at the expense of granulocytes (β =-0.876 [95% CI:-1.046 to-0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability. Conclusions: Collectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy.
AB - Aim: Preclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects. Methods and results: A multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (β = 0.131 [95% CI: 0.036-0.225]; P = 0.007), at the expense of granulocytes (β =-0.876 [95% CI:-1.046 to-0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability. Conclusions: Collectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy.
KW - Atherosclerosis
KW - Haematopoiesis
KW - Hypercholesterolaemia
KW - Monocytes
KW - Trained immunity
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85120375396&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/eurheartj/ehab465
DO - https://doi.org/10.1093/eurheartj/ehab465
M3 - Article
C2 - 34343254
SN - 0195-668X
VL - 42
SP - 4309
EP - 4320
JO - European Heart journal
JF - European Heart journal
IS - 42
ER -