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

Area of Science:

• Immunology
• Metabolic pathways
• Cardiovascular disease

Background:

• Translocated lipopolysaccharide (LPS) activates monocytes via TLR4, potentially increasing cardiovascular disease (CVD) risk in HIV patients.
• Mammalian target of rapamycin (mTOR) pathway is involved in immune cell inflammatory responses.

Purpose of the Study:

• To investigate the role of mTOR activity in LPS-stimulated monocyte production of pro-inflammatory cytokines and tissue factor (TF).
• To explore the metabolic mechanisms underlying mTOR's influence on monocyte inflammatory responses.

Main Methods:

• Multi-omics analyses of primary human monocytes.
• Treatment with catalytic mTOR inhibitors (mTORi).
• Assessment of cytokine (IL-1β, IL-6) and TF production.
• Analysis of NF-κB transcriptional activity and intracellular NAD+ levels.

Main Results:

• mTOR activation limits the abundance of pro-inflammatory cytokines and TF in monocytes.
• mTOR inhibition enhanced LPS-induced IL-1β, IL-6, and TF production.
• mTOR inhibition increased NF-κB-driven transcription of F3 (TF) and restricted intracellular NAD+ availability via decreased salvage pathway synthesis.

Conclusions:

• mTOR plays a restraining role in the LPS-induced transcriptional response of monocytes.
• A novel metabolic mechanism highlights mTOR-mediated regulation of monocyte inflammatory and pro-coagulant responses.
• Findings may inform strategies to mitigate coagulopathy risk in inflammatory conditions, particularly in HIV-positive individuals.