Filipe S. Pereira-Dutra , Julia Cunha Santos , Ellen Kiarely Souza , Rodrigo Vieira Savi , Tamyris S. Souza , Helen Gil , Hugo Espinheira-Silva , Felipe Ferraro-Moreira , Guilherme Iack , Tamires Cunha-Fernandes , Tathiany Igreja-Silva , Lohanna Palhinha , Mariana Macedo Campos , Ester Fernanda Terra Souza , Amanda França Cordeiro , Pablo Andrade-dos-Santos , Douglas Mathias Oliveira , Vinicius Soares Cardoso , Matheus A. Rajão , Livia Teixeira , Patrícia T. Bozza
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引用次数: 0
Abstract
Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that E. coli-infection trigger immunometabolic reprogramming and LD accumulation in murine macrophages (BMDM). Moreover, purified LDs from LPS-stimulated and E. coli-infected macrophages exhibited direct E. coli anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE2, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in E. coli-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE2, LTB4, and RvD1) in the peritoneum. Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.
期刊介绍:
Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism.
Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential.
The journal addresses a range of topics, including:
- Energy Expenditure and Obesity
- Metabolic Syndrome, Prediabetes, and Diabetes
- Nutrition, Exercise, and the Environment
- Genetics and Genomics, Proteomics, and Metabolomics
- Carbohydrate, Lipid, and Protein Metabolism
- Endocrinology and Hypertension
- Mineral and Bone Metabolism
- Cardiovascular Diseases and Malignancies
- Inflammation in metabolism and immunometabolism