Inflammation reprogramming and immunomodulation: Next-generation treatments for atherosclerosis

Abstract

The current generation of highly successful atherosclerosis treatments, such as low-density lipoprotein (LDL)-cholesterol reduction, blood pressure management, and smoking cessation, has largely focused on ameliorating factors perceived to drive incident disease and its complications. The adverse contributions of these factors have typically been identified through epidemiological studies. The therapeutic strategies that arose in response focused on risk factors for disease development and tended to overlook the fact that patients already have established disease, by the time of presentation. However, by capitalizing on contemporary biological knowledge and technologies, it is becoming increasingly possible to shift from a model based on population-derived risk factor management to next-generation treatments (including monoclonal antibodies, small interfering RNA [siRNA], mRNA, epigenetic reprogramming, and gene editing) for atherosclerosis that are tailored to patient-level disease processes, informed by mechanistic characterization, offer potential to reverse or regress disease, and incorporate systems-level interventions that extend beyond the atherosclerotic plaque.

Keywords: atherosclerosis; atherosclerosis regression; clonal hematopoiesis; diabetes; epigenetic; inflammation; therapeutics; trained immunity.

Graphical abstract

Figure 1

Processes driving atherosclerosis and opportunities for therapeutic intervention In the top left, the arterial wall is shown, highlighting the recruitment of immune cells such as monocytes and their differentiation into macrophage foam cells, along with the activation of T helper (Th) cells and B cells. Vascular cell adhesion molecule (VCAM) expression and the production of pro-inflammatory cytokines, including interleukin-1 (IL-1) and interleukin-6 (IL-6), contribute to the propagation of vascular inflammation. This section highlights where processes of inflammation can be targeted by interventions to ameliorate disease progression. The top right of the figure depicts mechanisms that promote the resolution of inflammation and the healing of atherosclerotic plaques. Regulatory T cells (Tregs) and regulatory B cells (Bregs) are involved in suppressing excessive immune responses, supporting plaque stabilization and repair. The liver is shown (bottom left) as a key organ in both the production of atherogenic apolipoprotein B (ApoB)-containing lipoproteins and the clearance of low-density lipoprotein cholesterol (LDL-C) via the low-density lipoprotein receptor (LDLR). Therapeutic approaches such as those targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) enhance LDL clearance. Systemic inflammation is often measured by levels of C-reactive protein (CRP), which is made by the liver. The bone marrow (bottom right) is increasingly recognized as a contributor to atherosclerosis and its complications. Clonal hematopoiesis, particularly involving mutations in genes ten-eleven translocation methylcytosine dioxygenase 2 (TET2) and DNA methyltransferase 3A (DNMT3A), is potentially causally related to atherogenesis. These processes, together with trained immunity and enhanced myelopoiesis, amplify systemic and vascular inflammation.