Chronic, unresolved inflammation is a feature of aging, and an important contributing cause of many age-related conditions. It is an inappropriate and damaging overactivation of the immune system, provoked by senescent cell signaling and various other forms of cell and tissue damage characteristic of aging. Why not just work to consistently suppress inflammation, then? The answer is that short-term inflammation is very important to health. It is needed in wound healing, destruction of potentially cancerous cells, and to fight off pathogens, and all of that remains true even in patients suffering from chronic inflammation throughout the body. Existing immunosuppressant therapies, such as the biologic drugs deployed to treat autoimmune conditions, have unpleasant long-term effects and make patients more vulnerable precisely because they have broad suppressive effects on the operation of the immune system.
Is it possible to be more selective, and only suppress the unwanted inflammatory signaling? In principle, yes. In practice, the immune system and its signaling is enormously complicated. That complexity is further quite different from tissue to tissue and situation to situation. Making inroads towards better immune suppression, more narrowly focused, with fewer side-effects, is very labor intensive. There are only so many researchers, only so much funding. Nonetheless, some progress is being made, as today's open access paper illustrates. The authors report on targeting inflammatory signaling that is more specifically associated with atherosclerosis than is the case for past attempts. This is an incremental advance, a narrowing of the target, and seems likely to still have some negative side-effects.
In atherosclerosis, fatty deposits called plaques form in blood vessel walls, narrowing and weakening the vessels. This occurs because the macrophage cells responsible for clearing up this sort of damage become overwhelmed. They try to clear out lipids from the plaques, become engorged, turn into foam cells, signal for other macrophages to come and help, and die, adding their mass to the plaque. Chronic inflammatory signaling is one aspect of the aging body that contributes to macrophage dysfunction, and it is that contribution that the approach described here seeks to remove.
Unfortunately, it seems likely that inflammatory signaling isn't the largest influence, in that reducing inflammation has been shown by other researchers to only have a small effect on existing plaque size. (This is while being possible, as shown here, to do better than this at reducing the development of plaques over time - but many approaches do quite well at prevention in mouse models. Reversal is the challenge). Reducing inflammation reverses existing plaques to about the same degree (less than 10%) that is produced by the use of statin drugs to lower blood cholesterol. The incapacity of macrophages appears more likely to be largely due to the presence of oxidized cholesterols or local excesses of cholesterol in the plaques.
A Repair Biotechnologies preclinical study reversed plaque size by nearly 50% via the approach of removing cholesterol directly from plaques, a considerably larger outcome than has been achieved by targeting either blood cholesterol or inflammation. Hopefully the Underdog Pharmaceuticals approach of sequestering 7-ketocholesterol from plaques will further prove the thesis by also doing well in vivo.
Chemokines are chemotactic cytokines that orchestrate cell trafficking and behavior in homeostasis and disease. Chemokines are pivotal players in various inflammatory diseases, including atherosclerosis. Therapeutic anti-cytokine approaches are successfully used in several inflammatory diseases and the positive results obtained with an interleukin-1β (IL-1β)-blocking antibody in the CANTOS trial have validated the inflammatory paradigm of atherosclerosis in humans and demonstrated the potential utility of anti-inflammatory drugs in patients with atherosclerotic disease. However, CANTOS also highlighted the need for molecular strategies with improved selectivity and less side effects.
While anti-chemokine strategies such as antibodies or small molecule drugs (SMDs) have been established, targeting a specific chemokine/receptor axis remains challenging due to the promiscuity in the chemokine network. In addition to antibodies and SMDs, soluble receptor-based approaches have proven as a powerful anti-cytokine strategy in inflammatory/immune diseases. For example, soluble tumor necrosis factor-receptor-1 (TNFR1)-based drugs are in clinical use for rheumatoid arthritis. However, soluble receptor-based approaches are not established for chemokine receptors.
Macrophage migration-inhibitory factor (MIF) is an evolutionarily conserved, multi-functional inflammatory mediator that is structurally distinct from other cytokines. We reasoned that designing CXCR4 ectodomain-derived peptides mimicking its interaction surface with MIF might be a promising approach to develop receptor-selective MIF inhibitors. Moreover, as the CXCL12/CXCR4 pathway exhibits critical homeostatic functions in resident arterial endothelial and smooth muscle cells and has a critical atheroprotective role, we aimed to generate CXCR4 mimics specific for MIF/CXCR4, while sparing CXCL12 pathways. Such mimics would be soluble chemokine receptor ectodomain-based inhibitors with receptor- and agonist-selective targeting properties. This approach would address current gaps in tailored chemokine-selective targeting strategies and receptor-specific MIF therapeutics in inflammatory and cardiovascular diseases.
We here report on engineered CXCR4 ectodomain-derived peptide mimics that selectively bind to the atypical chemokine MIF but not to CXCL12. Signaling experiments, chemotaxis, foam cell formation, and leukocyte recruitment studies in vitro and in the atherosclerotic vasculature demonstrate that such mimics can act as agonist-specific anti-atherogenic compounds, blocking CXCR4-mediated atherogenic MIF activities, while sparing CXCL12 and protective MIF/CD74-dependent signaling in cardiomyocytes. We show that our CXCR4 mimic is not only enriched in atherosclerotic plaque tissue in a MIF-specific manner in mouse and human lesions, but functionally protects from lesion development and atherosclerotic inflammation in an atherogenic Apolipoprotein e-deficient (Apoe-/-) model in vivo.