Targeting mTOR in myeloid cells prevents infection-associated inflammation

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. <i>In vitro</i>, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the <i>in vivo</i> effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using <sup>18</sup>F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

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Journal
iScience
Published
2025-03-04
DOI
https://doi.org/10.1016/j.isci.2025.112163
Citations
6
Primary Topic
Immune cells in cancer
Type
article
Field-Weighted Citation Impact
4.78

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Targeting mTOR in myeloid cells prevents infection-associated inflammation

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Targeting mTOR in myeloid cells prevents infection-associated inflammation

Jeroen Deckers, Thijs J. Beldman, Michael Schotsaert, Bas van Genabeek, Eliane E.S. Brechbühl, Mihai Gheorghe Netea, Mandy M. T. van Leent, Leo A. B. Joosten, Serge H. M. Söntjens, Sebastian A. Sarlea, Niels Peter Riksen, Geoffrey Prévot, Zhenhua Zhang, Willem J. M. Mulder, Ewelina Kluza, Ryan E. Temel, Mumin Ozturk, Musa M. Mhlanga, Roy van der Meel, Raphaël Duivenvoorden, Tom Anbergen, Yuri van Elsas, Esther Lutgens, Alexander Maier, Yohana Camila Antunes Frederico, Abraham J. P. Teunissen, Henk M. Janssen, Bram Priem, Judit Morlà‐Folch, Zahi Adel Fayad, Jazz Munitz, Freek J. M. Hoeben, Wenchao Li, Yang Li, William Wang, Lei Cai, Athanasios Ziogas, Jessica Fernandes, Joost H. C. M. Kreijtz, Evangelos J. Giamarellos‐Bourboulis, Gagandeep Singh, Muhammed D. Aksu, Glenn A O Cremers
article en
6 citations

Abstract

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. <i>In vitro</i>, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the <i>in vivo</i> effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using <sup>18</sup>F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

iScienceVol. 28(4)
Mayo Clinic (US), University of Bonn (DE), University of Kentucky (US), Radboud University Nijmegen (NL), University of Freiburg (DE), National and Kapodistrian University of Athens (GR), Iuliu Hațieganu University of Medicine and Pharmacy (RO), University of Cambridge (GB), Discovery Centre (CA), Cancer Research UK (GB), University Medical Center (US), Radboud University Medical Center (NL), Radboud Institute for Molecular Life Sciences (NL), Mayo Clinic in Arizona (US), SyMO-Chem (Netherlands) (NL), Centre for Individualised Infection Medicine (DE), Center for Experimental and Clinical Infection Research (DE), Eindhoven University of Technology (NL), Icahn School of Medicine at Mount Sinai (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Fondation Leducq, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Horizon 2020, National Institute of Allergy and Infectious Diseases, H2020 European Research Council, NHLBI Division of Intramural Research, HORIZON EUROPE Health
Good health and well-being
Openalex Percentile: Top 5%
Immune cells in cancer
4.78
DOIOpen Access PDFOpenAlex
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