RT Journal Article
T1 Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3
A1 Salloum, Zeina
A1 Dauner, Kristin
A1 Yun-feng, Li
A1 Verma, Neha
A1 Valdivieso González, David
A1 Almendro Vedia, Víctor G.
A1 Almendro Vedia, Víctor Galileo
A1 Zhang, John D
A1 Nakka, Kiran
A1 Xi Chen, Mei
A1 McDonald, Jeffrey
A1 Corley, Chase D
A1 Sorisky, Alexander
A1 Song, Bao-Liang
A1 López Montero, Iván
A1 Luo, Jie
A1 Dilworth, Jeffrey F
A1 Zha, Xiaohui
AB Statins are known to be anti-inflammatory, but the mechanism remains poorly understood. Here, we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane and changes the proton gradient in the mitochondria. This activates nuclear factor kappa-B (NF-κB) and Jmjd3 expression, which removes the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (M1), macrophages, either treated with statins in vitro or isolated from statin-fed mice, express lower levels proinflammatory cytokines than controls, while  augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL-4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.
PB eLife Sciences Publications, Ltd
YR 2024
FD 2024-04-11
LK https://hdl.handle.net/20.500.14352/115521
UL https://hdl.handle.net/20.500.14352/115521
LA eng
NO Salloum Z, Dauner K, Li YF, Verma N, Valdivieso-González D, Almendro-Vedia V, Zhang JD, Nakka K, Chen MX, McDonald J, Corley CD, Sorisky A, Song BL, López-Montero I, Luo J, Dilworth JF, Zha X. Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3. Elife. 2024 Apr 11;13:e85964. doi: 10.7554/eLife.85964. PMID: 38602170; PMCID: PMC11186637.
NO Comunidad Autónoma de Madrid
NO Fundación del Corazón y los Accidentes Cerebrovasculares de Canadá
DS Docta Complutense
RD 6 abr 2025