Abstract
Background and aimsAtherosclerosis is a chronic inflammatory disease of medium and large vessels and is typically characterized by the predominant accumulation of low-density lipoprotein (LDL)-cholesterol inside macrophages that reside in the vessel walls. Previous studies clearly demonstrated an association specifically between the oxidized type of LDL (oxLDL) and atherosclerotic lesion formation. Further observations revealed that these atherosclerotic lesions displayed enlarged, lipid-loaded lysosomes. By increasing natural antibodies against oxLDL, pneumococcal vaccination has been shown to reduce atherosclerosis in LDL receptor knockout (Ldlr−/−) mice. Relevantly, loss of the lysosomal membrane protein Niemann-Pick Type C1 (NPC1) led to lysosomal accumulation of various lipids and promoted atherosclerosis. Yet, the importance of lysosomal oxLDL accumulation inside macrophages, compared to non-modified LDL, in atherosclerosis has never been established. MethodsBy transplanting NPC1 bone marrow into lethally irradiated Ldlr−/− mice, a hematopoietic mouse model for lysosomal cholesterol accumulation was created. Through injections with heat-inactivated pneumococci, we aimed to demonstrate the specific contribution of lysosomal oxLDL accumulation inside macrophages in atherosclerosis development. ResultsWhile there were no differences in plaque morphology, a reduction in plaque size and plaque inflammation was found in immunized NPC1mut-transplanted mice, compared to non-immunized NPC1mut-transplanted mice. ConclusionsLysosomal oxLDL accumulation within macrophages contributes to murine atherosclerosis. Future intervention strategies should focus specifically on preventing oxLDL, unlike non-modified LDL, from being internalized into lysosomes. Such an intervention can have an additive effect to current existing treatments against atherosclerosis.
Highlights
Our results demonstrate that pneumococcal immunization can modulate atherogenesis in hematopoietic Niemann-Pick Type C1 (NPC1)-deficient low-density lipoprotein (LDL) receptor knockout (LdlrÀ/À) mice
While previous studies showed that pneumococcal immunization led to reduced lysosomal cholesterol accumulation [12], the current findings demonstrate the specific importance of oxidized LDL (oxLDL) within lysosomes in atherosclerosis development
The aim of this study was to demonstrate the contribution of lysosomal oxLDL accumulation, rather than non-modified LDL, to atherosclerosis, by exclusively preventing the macrophagemediated uptake and subsequent storage of oxLDL in NPC1 mutant (NPC1mut)-tp mice
Summary
Natural antibodies targeted at oxLDL (EO6) were shown to be abundantly present within atherosclerotic lesions [9,10] In line with these observations, our group and others demonstrated that a pneumococcal-induced immune response against the phosphorylcholine (PC) epitope, present on oxLDL, leads to diminished atherosclerosis development and hepatic inflammation [11,12]. Despite the fact that several studies found that NPC1 plays an important role in atherosclerosis, and that a number of in vitro studies clearly demonstrated that it is oxLDL that accumulates inside lysosomes of macrophages [19,20], the specific contribution of lysosomal oxLDL compared to non-modified LDL was neglected in these studies and has never been established in vivo [21e23].
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