Interplay between lipids, leukocytes, and inflammation

Promotion A. Groenen

Cardiovascular disease (CVD) is the leading cause of mortality worldwide and atherosclerosis is the primary underlying cause. Elevated blood leukocyte levels are associated with increased CV risk. Studies in animal models have shown that high-density lipoprotein (HDL) suppresses leukocytosis. We found that HDL-cholesterol and large HDL particles are negatively associated with blood leukocyte counts in individuals of the Lifelines DEEP cohort, suggesting human relevance of the findings in mice. Further, the research of Anouk Groenen showed that elevated blood leukocyte counts in patients with diabetes, and particularly blood neutrophils and monocytes, are associated with accumulation of advanced glycation end products, as measured non-invasively via skin autofluorescence in the Lifelines cohort. We then focused on inborn errors of metabolism and mechanisms that affect leukocyte counts. We found that a Niemann-Pick C1 mutation that enhances lysosomal cholesterol accumulation, induces stem cell mobilization to the spleen, which may contribute to splenomegaly and production of leukocytes by the spleen.

We subsequently investigated the link between risk factors for CVD and inflammation. We found that production of lipoprotein(a) [Lp(a)], a risk factor for CVD, was positively associated with plasma levels of pro-inflammatory interleukin (IL)-6 and IL-18. In addition, ageing is a major risk factor for CVD. Ageing is associated with non-resolving inflammation. During ageing, levels of specialized pro-resolving mediators (SPMs), particularly resolvin D1 (RvD1), decrease. Another hallmark of ageing is cellular senescence. We found that RvD1 treatment to old mice decreased macrophage senescence and inflammation. These data suggest that increasing SPM levels in humans may have beneficial clinical effects.