mTOR regulation of metabolism limits LPS-induced monocyte inflammatory and procoagulant responses

• Published in: Communications biology Vol. 5; no. 1; p. 878
• Main Authors: Lund, Nina C., Kayode, Yetunde, McReynolds, Melanie R., Clemmer, Deanna C., Hudson, Hannah, Clerc, Isabelle, Hong, Hee-Kyung, Brenchley, Jason M., Bass, Joseph, D’Aquila, Richard T., Taylor, Harry E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.08.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 631/250/2504/342; 631/250/255/1901; Biology; Biomedical and Life Sciences; Cardiovascular diseases; Cytokines; HIV; Human immunodeficiency virus; Humans; IL-1β; Inflammation; Interleukin 6; Life Sciences; Lipopolysaccharides; Metabolic pathways; Metabolism; Monocytes; NF-κB protein; Thromboplastin; Tissue factor; TLR4 protein; Toll-like receptors; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03804-z

Translocated lipopolysaccharide (LPS) activates monocytes via TLR4 and is hypothesized to increase cardiovascular disease risk in persons living with HIV. We tested whether mTOR activity supports LPS-stimulated monocyte production of pro-inflammatory cytokines and tissue factor (TF), as it propels the inflammatory response in several immune cell types besides monocytes. However, multi-omics analyses here demonstrate that mTOR activates a metabolic pathway that limits abundance of these gene products in monocytes. Treatment of primary human monocytes with catalytic mTOR inhibitors (mTORi) increased LPS-induced polyfunctional responses, including production of IL-1β, IL-6, and the pro-coagulant, TF. NF-κB-driven transcriptional activity is enhanced with LPS stimulation after mTORi treatment to increase expression of F3 (TF). Moreover, intracellular NAD + availability is restricted due to decreased salvage pathway synthesis. These results document mTOR-mediated restraint of the LPS-induced transcriptional response in monocytes and a metabolic mechanism informing strategies to reverse enhanced risk of coagulopathy in pro-inflammatory states. mTOR limits the activation of an inflammatory gene response in monocytes. Inhibitors of mTOR enhance NF-κB-driven transcription in LPS-stimulated monocytes while depleting NAD + through effects on the salvage pathway.