Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel walls, distorting, narrowing, and weakening the blood vessels. This ultimately leads to the major structural failure of a stroke or heart attack, in which a vital blood vessel ruptures or is blocked. Lipids, such as cholesterols, are carried in the blood stream throughout life, associated with low-density lipoprotein (LDL) particles. The innate immune cells known as macrophages are responsible for removing cholesterol from blood vessel walls via the processes of reverse cholesterol transport: macrophages ingest the cholesterol and pass it on to high-density lipoprotein (HDL) particles, which carry it back to the liver for excretion.
In youth, reverse cholesterol transport keeps blood vessels in good shape. With age, however, an increasing fraction of lipids become oxidized and damaged. This is in part a consequence of mitochondrial dysfunction and increasing chronic inflammation, leading to more oxidizing molecules in the body. Oxidized lipids, even in comparatively small amounts, cause macrophages to become dysfunctional, inflammatory, and sometimes senescent. This degrades the effectiveness of their activities, and leads to macrophage death. The fatty atherosclerotic plaques in blood vessels are in large part the debris of dead macrophages, in addition to lipids and oxidized lipids.
The growth of atherosclerotic plaques is thus a feedback loop, in which macrophages are overwhelmed by oxidized cholesterol, and their struggles attract more macrophages that attempt (and fail) to assist in clearing up the issue. Any signaling or chronic inflammation that induces more macrophages into a pro-inflammatory state rather than a pro-regenerative state will tend to accelerate the progression of atherosclerosis, either by calling in more macrophages, or by making macrophages less effective at reverse cholesterol transport.
That the state of macrophages can influence aging and age-related disease has become a topic of great interest in the research community in recent years, and not just in the context of atherosclerosis. Many age-related conditions have a strong inflammatory component, and it is possible to argue that in all such cases, this inflammation detrimentally affects the activities of macrophages. Researchers divide macrophage populations into the M1, inflammatory and aggressive phenotype and M2, pro-regenerative phenotypes. Both are needed, but with age, the balance shifts too far towards M1, characteristic of the rising chronic inflammation that takes place in later life. A variety of potential therapeutic approaches have been developed in recent years that aim to shift macrophages into the M2 phenotype, to override the signaling that leads them to adopt the M1 phenotype. The example here is one of the more recent ones.
In recent years, different approaches have been developed to counteract the progression of vascular atherosclerosis, including cholesterol-level lowering and inflammation modulation. Owing to the large numbers of inflammatory molecular and cellular mediators, it is unlikely that blockade of a single cytokine will be therapeutically effective. Long-living individuals (LLIs) delay or escape atherosclerosis-related cardiovascular disease (CVD). We have previously found that LLIs are enriched for a longevity-associated variant (LAV) in BPI fold containing family B, member 4 (BPIFB4).
We report here new exciting results on the pleiotropic activity of LAV-BPIFB4 on different mechanisms of the atherogenic process. These benefits were not associated with changes in the lipid profile. In addition, we provide ex vivo and in vitro evidence that these beneficial actions may extend to human vasculature until to be inversely associated to subclinical index of atherosclerosis in selected patients. Mechanistically, the effects of LAV-BPIFB4 seem to be attributable to a CXCR4-dependent mechanism.
LAV-BPIFB4 gene therapy succeeded in the two primary endpoints, namely improving endothelial dysfunction and reducing adverse vascular effects in ApoE knockout mice fed a high-lipid diet. Interestingly, LAV-BPIFB4 gene therapy did not affect the serum cholesterol profile, but it did contrast the ability of oxidized cholesterol to induce endothelial dysfunction by positively modulating the inflammatory/immune background of atherosclerosis. In line with this, LAV-BPIFB4 redistributed the pool of monocyte subpopulations, redirecting them towards a pro-resolving phenotype.
This was reflected by the increased abundance of CXCR4+Ly6C-high monocytes in bone marrow and spleen, the two major tissue reservoirs of monocytes available to mobilize towards injured tissues. In the margination process, CXCR4 is considered the retention force in the vasculature. Therefore, we speculate that the higher level of CXCR4 in blood Ly6C-high monocytes after LAV-BPIFB4 treatment in mice may finely tune the transit time into the circulation, completing a protective intravascular differentiation process. Consistent with their functionally distinct immunological roles, newly recruited Ly6C-high but not Ly6C-low monocytes uniquely differentiate into pro-resolving M2 macrophages, driving murine atherosclerotic regression at the early stages of the disease. Accordingly, we documented an enrichment of M2 splenic macrophages, which can contribute to dampen T cell activation and proliferation in a CXCR4-dependent manner. This latter result is in keeping with the reported ability of CXCR4 to promote the acquisition of the M2 phenotype in healthy monocyte-derived macrophages.