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Resolving neutrophils through genetic deletion of TRAM attenuate atherosclerosis pathogenesis
- Source :
- iScience, Vol 27, Iss 6, Pp 110097- (2024)
- Publication Year :
- 2024
- Publisher :
- Elsevier, 2024.
-
Abstract
- Summary: Systemic neutrophil dysregulation contributes to atherosclerosis pathogenesis, and restoring neutrophil homeostasis may be beneficial for treating atherosclerosis. Herein, we report that a homeostatic resolving subset of neutrophils exists in mice and humans characterized by the low expression of TRAM, correlated with reduced expression of inflammatory mediators (leukotriene B4 [LTB4] and elastase) and elevated expression of anti-inflammatory resolving mediators (resolvin D1 [RvD1] and CD200R). TRAM-deficient neutrophils can potently improve vascular integrity and suppress atherosclerosis pathogenesis when adoptively transfused into recipient atherosclerotic animals. Mechanistically, we show that TRAM deficiency correlates with reduced expression of 5-lipoxygenase (LOX5) activating protein (LOX5AP), dislodges nuclear localization of LOX5, and switches the lipid mediator secretion from pro-inflammatory LTB4 to pro-resolving RvD1. TRAM also serves as a stress sensor of oxidized low-density lipoprotein (oxLDL) and/or free cholesterol and triggers inflammatory signaling processes that facilitate elastase release. Together, our study defines a unique neutrophil population characterized by reduced TRAM, capable of homeostatic resolution and treatment of atherosclerosis.
- Subjects :
- Physiology
Immunology
Components of the immune system
Science
Subjects
Details
- Language :
- English
- ISSN :
- 25890042
- Volume :
- 27
- Issue :
- 6
- Database :
- Directory of Open Access Journals
- Journal :
- iScience
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.3513ac0002b1471c86347db97531e2f2
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.isci.2024.110097