Abstract 10491: CSL112 Suppresses Inflammation in Human Monocyte-Derived Macrophages

Abstract

Introduction: Inflammatory monocytes and tissue-resident macrophages play a key role in the pathogenesis of atherosclerosis. Pro-inflammatory macrophages promote formation of unstable plaques whereas anti-inflammatory macrophages contribute to plaque stabilization. HDL (high-density lipoprotein) stimulates atherosclerosis regression in animal models and alters the inflammatory properties of monocyte-derived cells present in plaques. CSL112, human apoA-I formulated with phosphatidylcholine, is currently in a phase 3 clinical trial (AEGIS-II [ApoA-I Event Reducing in Ischemic Syndromes II]) to prevent major adverse cardiovascular events (MACE) in the 90-day high-risk period following myocardial infarction. Objective: To investigate the effects of CSL112 on human monocyte-macrophage differentiation and pro-inflammatory macrophage activation. Methods: Human blood monocytes from healthy donors were differentiated into macrophages in the absence or presence of CSL112, and then treated with/without the toll-like receptor 2/1 agonist P3CSK4. Gene expression analysis was performed using RNA sequencing technology; secreted cytokines were measured by ELISA. Results: CSL112 did not affect macrophage maturation or cause macrophage polarization towards the M1 or M2 phenotype in the absence of an inflammatory stimulus. After P3CSK4 stimulation, CSL112 exerted broad anti-inflammatory effects by significantly modulating the expression of multiple genes implicated in atherosclerosis. Specifically, CSL112 reduced gene and protein expression of CCL2, CCL4, TNFα and IL-6, decreased the expression of membrane bound receptor expressed on myeloid cells 1 (TREM-1) and inhibited the release of soluble TREM-1. Additionally, CSL112 suppressed P3CSK4-induced IL-18 secretion, while upregulated the expression of IL-18 binding protein, a natural antagonist of IL-18. Conclusion: Our findings demonstrate anti-inflammatory effects of CSL112 that may stabilize vulnerable atherosclerotic plaques and potentially contribute to reduction in MACE in the subacute period following myocardial infarction.