Trained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?

Obesity, a chronic inflammatory disorder, is the most prevalent modifiable risk factor for cardiovascular disease throughout the life-course; long-term outcomes following lifestyle interventions have generally been disappointing. Inhibition of inflammation has been shown to decrease cardiovascular risk in patients with a residual inflammatory risk. Recent studies have demonstrated that the innate immune system can adopt a long-term memory (trained immunity) after a previous encounter with a stimulus, resulting in an increased response upon secondary stimulation. Monocytes from patients with atherosclerosis have a trained immune phenotype. In obesity, a state of dyslipidemia, endotoxemia, and increased plasma cytokines and adipokines is likely to induce trained immunity. Non-immune cells can also be trained, indicating a possible role for adipocyte memory in chronic inflammation. Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways. Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways. cytokines secreted by the adipose tissue, such as adiponectin and leptin. protective adipose tissue-derived hormone with insulin-sensitizing effects. a live-attenuated vaccine used against tuberculosis. the clinical manifestation of atherosclerosis, usually from compromised blood supply to key organs, such as the heart and brain. Clinically manifests as ischemic heart disease, heart failure, stroke, and peripheral vascular disease. abnormalities in the small vessels in the brain. the presence of LPS in the bloodstream due to leakage of Gram-negative bacterial particles from the gut. short regions of DNA regulating the likelihood of gene transcription. Often modified by epigenetic changes. the regulation of DNA transcription without affecting the DNA sequence itself, by histone modifications, noncoding RNA, and/or DNA methylation. genetic disorder resulting in high levels of LDL-cholesterol and early cardiovascular disease. a form of inflammatory arthritis that develops in people with high levels of uric acid in the blood. a glycoprotein that acts as a growth factor for the myeloid lineage. also called hematopoietic stem cells (HSCs); cells in the bone marrow that give rise to all leukocytes and lymphocytes in the circulation. proteins in the nucleus that package DNA. intracellular pathways, including glycolysis or oxidative phosphorylation, to produce energy (ATP) for cellular homeostasis. a hormone produced by the adipose tissue regulating hunger in the hypothalamus. accumulation of lipids in nonadipose tissue, leading to cytotoxicity and cell death. a central regulator of cellular metabolism, growth, and proliferation, processing a broad range of environmental and nutritional stimuli. central brain structure involved in appetite and satiety control. monocytes can be classified into classical, intermediate, and nonclassical subsets according to their surface protein constellation. Several subsets have been associated with increased risk of CVD. HSCs that are reprogrammed to produce myeloid cells (granulocytes and monocytes) and less lymphocytes (B and T cells). resident macrophages originate from yolk sac-derived progenitors, reside in tissues, and perform homeostatic functions. They self-maintain locally. transmembrane proteins belonging to the pattern recognition receptor family of the innate immune system, signaling a broad range of pathogens. obesity, diabetes, hypertension, smoking, and hypercholesterolemia are thought to account for 60–90% of CVD risk.