Atherosclerosis is a leading cause of global morbidity and mortality. Cholesterol crystal embolism (CCE) in advanced atherosclerosis can lead to acute kidney injury (AKI) through ischemic cortical necrosis. However, a single-cell atlas of the CCE kidney remains incomplete, impeding rational therapeutic design. In a C57BL/6J mouse CCE model generated by unilateral renal artery CC injection, single-cell transcriptomics revealed widespread changes across 17 kidney cell types. The differentially expressed genes (DEGs) varied markedly, with 1659 in the ascending loop of Henle and 1505 in proximal tubules, whereas only 7 were in dendritic cells. Cell-cell interaction analyses revealed a central role for C-C motif chemokine ligand (CCL)–C-C motif chemokine receptor 5 (CCR5) and macrophage migration inhibitory factor (MIF)–cluster of differentiation 74 (CD74) pathways in CCE formation and related outcomes, including vascular injury, AKI, and immune cell infiltration. Human kidney biopsies from patients with CCE showed CD74-positive staining near obstructed arteries with cholesterol clefts. Pharmacological inhibition of CCR5 or CD74 using maraviroc or milatuzumab, respectively, as well as their combined administration before CC injection, reduced vascular thrombosis and tissue damage without raising bleeding risk in the C57BL/6J mouse CCE model. Even when treatment was delayed by 2 hours postembolism, it still decreased complications like thrombotic angiopathy and AKI upon CCE. These findings highlight CCR5 and CD74 as potential therapeutic targets for CCE-related necroinflammation.
Shi et al. (2026) studied this question.