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

Nina C. Lund; Yetunde Kayode; Melanie R. McReynolds; Deanna C. Clemmer; Hannah Hudson; Isabelle Clerc; Hee Kyung Hong; Jason M. Brenchley; Joseph Bass; Richard T. D’Aquila; Harry Eugene Taylor

doi:10.1038/s42003-022-03804-z

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

Nina C. Lund, Yetunde Kayode, Melanie R. McReynolds, Deanna C. Clemmer, Hannah Hudson, Isabelle Clerc, Hee Kyung Hong, Jason M. Brenchley, Joseph Bass, Richard T. D’Aquila^*, Harry Eugene Taylor^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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.

Original language	English (US)
Article number	878
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03804-z
State	Published - Dec 2022

Funding

The authors would like to acknowledge the care provided by Heather Kendall, Joanna Swerczek, and their team at the NIH Animal Center. The authors are also grateful for the contributions of staff at the Third Coast CFAR Viral Pathogenesis Core, the Northwestern Metabolomics Developing Core, the RHLCCC Flow Cytometry Core Facility, and the NUSeq Core, with special thanks to Sixia Xiao, Peng Gao, Xinkun Wang, Ryan Embry, Matt Schipma, Alan Aalsburg, and Kara Pivarski. This work was supported by NIH grants, as follows: N.C. was supported by F30 AI131937 and T32GM008152, R.T.D. and H.E.T. were supported by P01 AI131346, H.K.H. and J.B. were supported by NIDDK grants R01DK090625, R01DK127800, R01DK050203, and R01DK113011, NIA grants P01AG011412 and R01AG065988, JDRF grant 17-2013-511, and the Chicago Biomedical Consortium S-007, and M.R.M. was supported by HHMI Hanna H. Gray Fellows program and Burroughs Wellcome Fund PDEP. Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. The content of this publication does not necessarily reflect the views or policies of DHHS, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional support from the Third Coast Center for AIDS Research (CFAR), an NIH funded center (P30 AI117943), is appreciated. H.E.T. was also supported by start-up funds from the State of New York and the Research Foundation for SUNY. The authors would like to acknowledge the care provided by Heather Kendall, Joanna Swerczek, and their team at the NIH Animal Center. The authors are also grateful for the contributions of staff at the Third Coast CFAR Viral Pathogenesis Core, the Northwestern Metabolomics Developing Core, the RHLCCC Flow Cytometry Core Facility, and the NUSeq Core, with special thanks to Sixia Xiao, Peng Gao, Xinkun Wang, Ryan Embry, Matt Schipma, Alan Aalsburg, and Kara Pivarski. This work was supported by NIH grants, as follows: N.C. was supported by F30 AI131937 and T32GM008152, R.T.D. and H.E.T. were supported by P01 AI131346, H.K.H. and J.B. were supported by NIDDK grants R01DK090625, R01DK127800, R01DK050203, and R01DK113011, NIA grants P01AG011412 and R01AG065988, JDRF grant 17-2013-511, and the Chicago Biomedical Consortium S-007, and M.R.M. was supported by HHMI Hanna H. Gray Fellows program and Burroughs Wellcome Fund PDEP. Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. The content of this publication does not necessarily reflect the views or policies of DHHS, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional support from the Third Coast Center for AIDS Research (CFAR), an NIH funded center (P30 AI117943), is appreciated. H.E.T. was also supported by start-up funds from the State of New York and the Research Foundation for SUNY.

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry, Genetics and Molecular Biology
Medicine (miscellaneous)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s42003-022-03804-z

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title = "mTOR regulation of metabolism limits LPS-induced monocyte inflammatory and procoagulant responses",

abstract = "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.",

author = "Lund, {Nina C.} and Yetunde Kayode and McReynolds, {Melanie R.} and Clemmer, {Deanna C.} and Hannah Hudson and Isabelle Clerc and Hong, {Hee Kyung} and Brenchley, {Jason M.} and Joseph Bass and D{\textquoteright}Aquila, {Richard T.} and Taylor, {Harry Eugene}",

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doi = "10.1038/s42003-022-03804-z",

language = "English (US)",

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AU - Lund, Nina C.

AU - Kayode, Yetunde

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AU - Clemmer, Deanna C.

AU - Hudson, Hannah

AU - Clerc, Isabelle

AU - Hong, Hee Kyung

AU - Brenchley, Jason M.

AU - Bass, Joseph

AU - D’Aquila, Richard T.

AU - Taylor, Harry Eugene

PY - 2022/12

Y1 - 2022/12

N2 - 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.

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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