Targeting mTOR in myeloid cells prevents infection-associated inflammation

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

doi:10.1016/j.isci.2025.112163

Targeting mTOR in myeloid cells prevents infection-associated inflammation

Yohana C. Toner, Jazz Munitz, Geoffrey Prevot, Judit Morla-Folch, William Wang, Yuri van Elsas, Bram Priem, Jeroen Deckers, Tom Anbergen, Thijs J. Beldman, Eliane E.S. Brechbühl, Muhammed D. Aksu, Athanasios Ziogas, Sebastian A. Sarlea, Mumin Ozturk, Zhenhua Zhang, Wenchao Li, Yang Li, Alexander Maier, Jessica C. FernandesGlenn A.O. Cremers, Bas van Genabeek, Joost H.C.M. Kreijtz, Esther Lutgens, Niels P. Riksen, Henk M. Janssen, Serge H.M. Söntjens, Freek J.M. Hoeben, Ewelina Kluza, Gagandeep Singh, Evangelos J. Giamarellos-Bourboulis, Michael Schotsaert, Raphaël Duivenvoorden, Roy van der Meel, Leo A.B. Joosten, Lei Cai, Ryan E. Temel, Zahi A. Fayad, Musa M. Mhlanga, Mandy M.T. van Leent, Abraham J.P. Teunissen, Mihai G. Netea, Willem J.M. Mulder (Corresponding author)

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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. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using ¹⁸F-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.

Original language	English
Article number	112163
Number of pages	18
Journal	iScience
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2025.112163
Publication status	Published - 18 Apr 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s)

Keywords

Biochemistry
Biological sciences
Immunology
Natural sciences

UN SDGs

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

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Toner, Y. C., Munitz, J., Prevot, G., Morla-Folch, J., Wang, W., van Elsas, Y., Priem, B., Deckers, J., Anbergen, T., Beldman, T. J., Brechbühl, E. E. S., Aksu, M. D., Ziogas, A., Sarlea, S. A., Ozturk, M., Zhang, Z., Li, W., Li, Y., Maier, A., ... Mulder, W. J. M. (2025). Targeting mTOR in myeloid cells prevents infection-associated inflammation. iScience, 28(4), Article 112163. https://doi.org/10.1016/j.isci.2025.112163

@article{cb9c086074c34bb8850a19855b61696f,

title = "Targeting mTOR in myeloid cells prevents infection-associated inflammation",

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. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-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.",

keywords = "Biochemistry, Biological sciences, Immunology, Natural sciences",

author = "Toner, {Yohana C.} and Jazz Munitz and Geoffrey Prevot and Judit Morla-Folch and William Wang and {van Elsas}, Yuri and Bram Priem and Jeroen Deckers and Tom Anbergen and Beldman, {Thijs J.} and Brechb{\"u}hl, {Eliane E.S.} and Aksu, {Muhammed D.} and Athanasios Ziogas and Sarlea, {Sebastian A.} and Mumin Ozturk and Zhenhua Zhang and Wenchao Li and Yang Li and Alexander Maier and Fernandes, {Jessica C.} and Cremers, {Glenn A.O.} and {van Genabeek}, Bas and Kreijtz, {Joost H.C.M.} and Esther Lutgens and Riksen, {Niels P.} and Janssen, {Henk M.} and S{\"o}ntjens, {Serge H.M.} and Hoeben, {Freek J.M.} and Ewelina Kluza and Gagandeep Singh and Giamarellos-Bourboulis, {Evangelos J.} and Michael Schotsaert and Rapha{\"e}l Duivenvoorden and {van der Meel}, Roy and Joosten, {Leo A.B.} and Lei Cai and Temel, {Ryan E.} and Fayad, {Zahi A.} and Mhlanga, {Musa M.} and {van Leent}, {Mandy M.T.} and Teunissen, {Abraham J.P.} and Netea, {Mihai G.} and Mulder, {Willem J.M.}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = apr,

day = "18",

doi = "10.1016/j.isci.2025.112163",

language = "English",

volume = "28",

journal = "iScience",

issn = "2589-0042",

publisher = "Cell Press",

number = "4",

}

Toner, YC, Munitz, J, Prevot, G, Morla-Folch, J, Wang, W, van Elsas, Y, Priem, B, Deckers, J, Anbergen, T, Beldman, TJ, Brechbühl, EES, Aksu, MD, Ziogas, A, Sarlea, SA, Ozturk, M, Zhang, Z, Li, W, Li, Y, Maier, A, Fernandes, JC, Cremers, GAO, van Genabeek, B, Kreijtz, JHCM, Lutgens, E, Riksen, NP, Janssen, HM, Söntjens, SHM , Hoeben, FJM , Kluza, E, Singh, G, Giamarellos-Bourboulis, EJ, Schotsaert, M, Duivenvoorden, R, van der Meel, R, Joosten, LAB, Cai, L, Temel, RE, Fayad, ZA, Mhlanga, MM, van Leent, MMT, Teunissen, AJP, Netea, MG & Mulder, WJM 2025, 'Targeting mTOR in myeloid cells prevents infection-associated inflammation', iScience, vol. 28, no. 4, 112163. https://doi.org/10.1016/j.isci.2025.112163

TY - JOUR

T1 - Targeting mTOR in myeloid cells prevents infection-associated inflammation

AU - Toner, Yohana C.

AU - Munitz, Jazz

AU - Prevot, Geoffrey

AU - Morla-Folch, Judit

AU - Wang, William

AU - van Elsas, Yuri

AU - Priem, Bram

AU - Deckers, Jeroen

AU - Anbergen, Tom

AU - Beldman, Thijs J.

AU - Brechbühl, Eliane E.S.

AU - Aksu, Muhammed D.

AU - Ziogas, Athanasios

AU - Sarlea, Sebastian A.

AU - Ozturk, Mumin

AU - Zhang, Zhenhua

AU - Li, Wenchao

AU - Li, Yang

AU - Maier, Alexander

AU - Fernandes, Jessica C.

AU - Cremers, Glenn A.O.

AU - van Genabeek, Bas

AU - Kreijtz, Joost H.C.M.

AU - Lutgens, Esther

AU - Riksen, Niels P.

AU - Janssen, Henk M.

AU - Söntjens, Serge H.M.

AU - Hoeben, Freek J.M.

AU - Kluza, Ewelina

AU - Singh, Gagandeep

AU - Giamarellos-Bourboulis, Evangelos J.

AU - Schotsaert, Michael

AU - Duivenvoorden, Raphaël

AU - van der Meel, Roy

AU - Joosten, Leo A.B.

AU - Cai, Lei

AU - Temel, Ryan E.

AU - Fayad, Zahi A.

AU - Mhlanga, Musa M.

AU - van Leent, Mandy M.T.

AU - Teunissen, Abraham J.P.

AU - Netea, Mihai G.

AU - Mulder, Willem J.M.

PY - 2025/4/18

Y1 - 2025/4/18

N2 - 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. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-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.

AB - 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. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-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.

KW - Biochemistry

KW - Biological sciences

KW - Immunology

KW - Natural sciences

UR - http://www.scopus.com/inward/record.url?scp=105000100029&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2025.112163

DO - 10.1016/j.isci.2025.112163

M3 - Article

C2 - 40177636

AN - SCOPUS:105000100029

SN - 2589-0042

VL - 28

JO - iScience

JF - iScience

IS - 4

M1 - 112163

ER -

Targeting mTOR in myeloid cells prevents infection-associated inflammation

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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