Deficiency of lncRNA MERRICAL abrogates macrophage chemotaxis and diabetes-associated atherosclerosis

• DOI: 10.1016/j.celrep.2024.113815
• Publication Date: 2024-02-29T15:32:41Z
• Authors: Jingshu Chen; Anurag Jamaiyar; Winona Wu; Yi Hu; Rulin Zhuang; Grasiele Sausen; Henry S. Cheng; Camila de Oliveir...; Daniel Pérez-Crem...; Aspasia Tzani; Michael G. McCoy; Carmel Assa; Samuel Eley; Vinay Randhawa; Kwangwoon Lee; Jorge Plutzky; Naomi M. Hamburg; Marc S. Sabatine; Mark W. Feinberg
• Keywords: Mice, Knockout; diabetes; Chemotaxis; Macrophages; Aortic Diseases; CP: Immunology; Atherosclerosis; Article; Plaque, Atherosclerotic; macrophages; Mice, Inbred C57BL; Mice; lncRNA; Receptors, LDL; Diabetes Mellitus; Animals; RNA, Long Noncoding; atherosclerosis; chemotaxis

Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of aortic intima in Ldlr−/− mice on a high-fat, high-sucrose-containing (HFSC) diet identifies macrophage-enriched nuclear long noncoding RNA (lncRNA), MERRICAL (macrophage-enriched lncRNA regulates inflammation, chemotaxis, atherosclerosis). expression increases by 249% intimal lesions during progression. lncRNA-mRNA pair genomic mapping reveals that positively correlates with chemokines Ccl3 Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl4 expression, inflammatory responses. Mechanistically, guides WDR5-MLL1 complex to activate CCL3 CCL4 transcription via H3K4me3 modification. deficiency HFSC diet-fed reduces lesion formation 74% sinus 86% descending aorta inhibiting leukocyte into wall pro-inflammatory These findings unveil regulatory mechanism whereby potently inhibits chemotactic responses, alleviating progression diabetes.