Endoplasmic Reticulum Stress Impairs Macrophage Efferocytosis via TRIB3-Rab27a Signaling and Exacerbates Atherosclerotic Plaque Necrosis

Defective clearance of apoptotic cells (efferocytosis) by macrophages is a key driver of atherosclerotic plaque necrosis which is associated with adverse clinical outcomes such as myocardial infarction and stroke. The mechanistic basis of defective efferocytosis in atherosclerotic plaque macrophages is not well understood. We show that hyperlipidemia and the consequent accumulation of lipids in macrophages triggers endoplasmic reticulum stress which directly impairs efferocytosis. Mechanistically, we demonstrate that lipid accumulation-induced activation of the ATF4 branch of the unfolded protein response pathway and the consequent upregulation of Tribbles pseudokinase 3 (TRIB3) triggers the downregulation of Rab27a resulting in impaired focal exocytosis of intracellular membrane pools towards the apoptotic cell-containing nascent phagosome. The resultant impairment in phagosome closure stalls the efferocytic process. Humans with the gain-of-function Q84R TRIB3 variant contain more TRIB3 in macrophages and display decreased efferocytosis efficiency. We confirm higher TRIB3 expression in vulnerable plaques of humans and show that hematopoietic cell-specific deletion of TRIB3 in high-fat diet fed atherosclerosis-prone mice improves lesional macrophage efferocytosis efficiency and decreases plaque necrosis. Overall, our findings highlight a novel role for the ATF4-TRIB3-Rab27a signaling axis in mediating defective efferocytosis in atherosclerosis and opens new avenues for targeting this pathway for atherosclerotic plaque stabilization.