Impact of cholesterol on proinflammatory monocyte production by the bone marrow

Abstract

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.

Monocyte and Macrophage Lipid Accumulation Results in Down-Regulated Type-I Interferon Responses

“…The study population, design, and further processing of these human study subjects and their samples have been extensively described ( 40 ). Briefly, untreated FH patients who indicated to start lipid-lowering therapy (statin, PCSK9 antibody, and/or ezetimibe) according to their treating physician were included.…”

LDL-cholesterol drives reversible myelomonocytic skewing in human bone marrow

“…6 Using an inherited genetic defect leading to an extreme condition of elevated plasma LDL-C, the study by Stiekema et al now provides the first genetic evidence of a role for LDL-C in HSPC expansion and myelomonocytic skewing in FH patients, with reversal by cholesterol-lowering therapies, including statins. 1 From previous studies, we have learned that reducing LDL-C by statin therapy decreases plasma levels of high-sensitivity C-reactive protein (hs-CRP), a standard marker of systemic inflammation, but residual inflammatory risk (hs-CRP >2 mg/L) persists. 15 However, blood monocyte counts and hs-CRP differently predict future CVD.…”

“…15 However, blood monocyte counts and hs-CRP differently predict future CVD. 16 In the EPIC-Norfolk Prospective Population Study (comprising 12 304 individuals), the positive correlation between plasma LDL-C and blood monocytes was adjusted for plasma hs-CRP levels, age, gender, smoking, and body mass index, 1 suggesting that LDL-C may enhance inflammatory and CVD risk via monocytosis independently of its effects on hs-CRP, and downstream of its role in HSPC expansion.…”

“…Using 10 untreated FH adult patients, Stiekema et al uniquely show a 1.4-fold expansion of CD34 þ HSPCs obtained from sternal BM aspiration in FH patients compared with age-and-gender-matched normocholesterolaemic controls. 1 Despite BM and blood monocyte counts being similar in FH patients and normocholesterolaemic controls, the authors identified a gene signature in BM CD34 þ HSPCs from FH patients promoting myelomonocytic skewing along with a promigratory profile, while the expression of genes involved in cell cycling was decreased, and there were differences in expression of genes that regulate metabolic flux. Based on this transcriptomic analysis, the authors proposed that perturbed oxidative phosphorylation (OXPHOS) could be due to a switch from glucose to fatty acid utilization (based on higher Pdk4 expression in HSPCs from FH patients compared with controls).…”

“…Based on this transcriptomic analysis, the authors proposed that perturbed oxidative phosphorylation (OXPHOS) could be due to a switch from glucose to fatty acid utilization (based on higher Pdk4 expression in HSPCs from FH patients compared with controls). 1 cycle makes intuitive sense when HSPCs enter differentiation, the down-regulation of gene sets related to Runx1-regulated HSPC differentiation is intriguing, because Runx1-deficient mice display lack of foetal liver haematopoiesis. However, in adult haematopoiesis, RUNX1 may dictate HSPC fate depending on the growth hormone environment.…”