Mechanisms of Trained Innate Immunity in oxLDL Primed Human Coronary Smooth Muscle Cells

Abstract

Objective: Damage and pathogen associated molecular patterns such as oxidized low-density lipoprotein (oxLDL) or bacillus Calmette-Guerin (BCG) vaccine can induce long term pro-inflammatory priming in monocytes and macrophages due to metabolic and epigenetic reprogramming—an emerging new concept called trained innate immunity. Vascular smooth muscle cells express pattern recognition receptors involved in trained innate immunity in monocytes. Here we investigated whether the mechanisms of trained innate immunity also control a proinflammatory phenotype in human coronary smooth muscle cells.Methods: Human coronary smooth muscle cells were primed with oxLDL or BCG for 24 h. After a resting time of 4 to 7 days, the cells were restimulated with either PAM3cys4, LPS or TNFα and cytokine production or mRNA expression were measured. Then, mechanisms of monocyte trained innate immunity were analyzed in smooth muscle cells, including receptors, intracellular pathways as well as metabolic and epigenetic reprogramming.Results: Priming with oxLDL or BCG lead to a significantly increased production of IL6, IL8 and MCP-1 following restimulation. OxLDL priming had little effect on the expression of macrophage or SMC marker genes. Proinflammatory priming of smooth muscle cells induced mTOR-HIF1α-signaling and could be blocked by mTOR-, TLR2-, and TLR4-inhibition. Finally, metabolic and epigenetic mechanisms of trained innate immunity in monocytes could be replicated in smooth muscle cells, including increased glucose consumption, lactate production, responsiveness to 6-fluoromevalonate and mevalonate treatment and inhibition of priming by the histone methyltransferase inhibitor methylthioadenosine (MTA).Conclusion: We demonstrate for the first time that mechanisms of the so called trained innate immunity control a proinflammatory phenotype in non-immune cells of the vascular wall. Our findings warrant further research into the specificity of trained innate immunity as an immune cell response as well as the mechanisms of vascular smooth muscle cells inflammation.

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

“…In addition, brief oxLDL stimulation also induces a persistent pro-inflammatory priming effect in cultured coronary smooth muscle cells (46). Interestingly, the mechanisms involved in this process were found to be somewhat similar to trained immunity induced in myeloid cells (46). Altogether, the establishment of a memory for previous encounters is an important trait of activated endothelial cells and smooth muscle cells in response to pro-atherogenic stimulation.…”

“…For example, vascular smooth muscle cells isolated from a mouse model of diabetes display a potential pro-atherogenic phenotype such as upregulated inflammatory gene expression, accelerated migration ability, and enhanced adhesion to monocytes, which persists ex vivo for relatively long periods (45). In addition, brief oxLDL stimulation also induces a persistent pro-inflammatory priming effect in cultured coronary smooth muscle cells (46). Interestingly, the mechanisms involved in this process were found to be somewhat similar to trained immunity induced in myeloid cells (46).…”

“…On a systems level, stimulated bone marrow progenitors undergo transcriptional, metabolic, and epigenetic remodeling, which facilitates their more robust secondary response, as well as that of their progeny cells, to subsequent challenges. In addition, recent findings also suggested that the induction of cellular memory in non-immune cells may share similar mechanisms with innate immune training (46). While a variety of exogenous and endogenous stimuli can induce trained immunity, our current knowledge about the underlying mechanisms is mainly based on studies investigating the induction of trained immunity by several model training stimuli including β-glucan, BCG vaccination, and oxLDL.…”

Oxidized cholesterol exacerbates toll-like receptor 4 expression and activity in the hearts of rats with myocardial infarction

“…27,28 OxLDL could be classified as damage-associated molecular pattern (DAMP). 29,30 DAMPs activate of smooth muscle cells and increased production of cytokines in response to restimulation. 29 Other studies demonstrated that inhibition of TLR4/MyD88/NFκB signaling pathway could improve the severity of MI and prevent cardiac remodeling.…”

“…29,30 DAMPs activate of smooth muscle cells and increased production of cytokines in response to restimulation. 29 Other studies demonstrated that inhibition of TLR4/MyD88/NFκB signaling pathway could improve the severity of MI and prevent cardiac remodeling. 31 We have recently reported that cardiac function in animals fed with high cholesterol and oxidized cholesterol diets before MI induction by isoproterenol considerably suppressed.…”