Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3
- Ottawa Hospital Research Institute, Canada
- Wuhan University, China
- Universidad Complutense de Madrid, Spain
- The University of Texas Southwestern Medical Center, United States
Abstract
Stains 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 ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (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.
Data availability
1. Sequencing data have been deposited in GEO under accession codes:GSE196187, GSE196188, GSE196189.2. All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Víctor G Almendro-Vedia
Iván López-Montero
Funding
Heart and Stroke Foundation of Canada (G-19-0026359)
- Xiaohui Zha
Canadian Institutes of Health Research (PJT-180504)
- Jeffrey F Dilworth
NIH Office of the Director (HL020948)
- Jeffrey G McDonald
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jalees Rehman, University of Illinois at Chicago, United States
Version history
- Received: January 5, 2023
- Accepted: March 13, 2024
- Accepted Manuscript published: April 11, 2024 (version 1)
- Accepted Manuscript updated: April 15, 2024 (version 2)
Copyright
© 2024, Salloum et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 312
- views
-
- 87
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3
eLife 13:e85964.
https://doi.org/10.7554/eLife.85964
Further reading
-
- Cell Biology
A new protocol can customize the flavor of lab-grown meat by controlling the level of fat deposited between muscle cells.
-
- Cancer Biology
- Cell Biology
Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the ‘Warburg effect’, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.
