Abstract
Abstract Macrophages undergo profound metabolic reprogramming in response to activation signals. However, the purpose and the mechanism of this reprogramming remains poorly understood. Cholesterol is an essential lipid molecule that modulates biochemical and biophysical properties of cellular membranes. Microbes have evolved strategies which specifically exploit the presence of membrane cholesterol to facilitate pathogenesis. Cholesterol-dependent cytolysin (CDC) are pore-forming toxins produced by gram-positive microorganisms that results in loss of membrane integrity, cellular dysfunction, and cell death. Herein, we delineate a unappreciated immune cell strategy that relies on rapid reprogramming of cholesterol homeostasis to avoid the deleterious effects CDCs. We show that interferon signals convey resistance to CDCs in myeloid cells by altering the availability of cholesterol in the plasma membrane (PM). Mechanistic studies reveal that resistance to CDCs occurs as a result of the movement of cholesterol from the PM to the endoplasmic reticulum (ER), and ultimately into an intracellular esterified pool. We also find that IFN-mediated inhibition of cholesterol synthesis is required to ensure maximal resistance to CDC challenge. Finally, we demonstrate that the IFN-mediated inhibition of cholesterol synthesis is dependent on production of the oxysterol, 25-hydroxycholesterol, and that the loss of CH25H renders mice more susceptible to CDC-mediated tissue damage. Together, these data provide evidence for remodeling of membrane lipid composition as a host defense strategy to bacterial toxins, and suggests that metabolic reprogramming of lipid architecture has significance beyond that of supporting immune function.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.