Systemic inflammation impairs myelopoiesis and interferon type I responses in humans

Farid Keramati; Guus P Leijte; Niklas Bruse; Inge Grondman; Ehsan Habibi; Cristian Ruiz-Moreno; Wout Megchelenbrink; Annemieke M Peters van Ton; Hidde Heesakkers; Manita E Bremmers; Erinke van Grinsven; Kiki Tesselaar; Selma van Staveren; Walter J van der Velden; Frank W Preijers; Brigit Te Pas; Raoul van de Loop; Jelle Gerretsen; Mihai G Netea; Hendrik G Stunnenberg; Peter Pickkers; Matthijs Kox

doi:10.1038/s41590-025-02136-4

Systemic inflammation impairs myelopoiesis and interferon type I responses in humans

Farid Keramati, Guus P Leijte, Niklas Bruse, Inge Grondman, Ehsan Habibi, Cristian Ruiz-Moreno, Wout Megchelenbrink, Annemieke M Peters van Ton, Hidde Heesakkers, Manita E Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter J van der Velden, Frank W Preijers, Brigit Te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G Netea, Hendrik G Stunnenberg^*Peter Pickkers, Matthijs Kox

^*Corresponding author for this work

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

1 Downloads (Pure)

Abstract

Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.

Original language	English
Article number	e1001304
Pages (from-to)	737–747
Number of pages	11
Journal	Nature immunology
Volume	26
Issue number	5
Early online date	18 Apr 2025
DOIs	https://doi.org/10.1038/s41590-025-02136-4
Publication status	Published - 2025

Access to Document

10.1038/s41590-025-02136-4Licence: CC BY

s41590-025-02136-4Final published version, 14.1 MBLicence: CC BY

Cite this

Keramati, F., Leijte, G. P., Bruse, N., Grondman, I., Habibi, E., Ruiz-Moreno, C., Megchelenbrink, W., Peters van Ton, A. M., Heesakkers, H., Bremmers, M. E., van Grinsven, E., Tesselaar, K., van Staveren, S., van der Velden, W. J., Preijers, F. W., Te Pas, B., van de Loop, R., Gerretsen, J., Netea, M. G., ... Kox, M. (2025). Systemic inflammation impairs myelopoiesis and interferon type I responses in humans. Nature immunology, 26(5), 737–747. Article e1001304. https://doi.org/10.1038/s41590-025-02136-4

@article{46d4dcce6f6d4774a67eb632e8d26131,

title = "Systemic inflammation impairs myelopoiesis and interferon type I responses in humans",

abstract = "Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.",

author = "Farid Keramati and Leijte, {Guus P} and Niklas Bruse and Inge Grondman and Ehsan Habibi and Cristian Ruiz-Moreno and Wout Megchelenbrink and {Peters van Ton}, {Annemieke M} and Hidde Heesakkers and Bremmers, {Manita E} and {van Grinsven}, Erinke and Kiki Tesselaar and {van Staveren}, Selma and {van der Velden}, {Walter J} and Preijers, {Frank W} and {Te Pas}, Brigit and {van de Loop}, Raoul and Jelle Gerretsen and Netea, {Mihai G} and Stunnenberg, {Hendrik G} and Peter Pickkers and Matthijs Kox",

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

year = "2025",

doi = "10.1038/s41590-025-02136-4",

language = "English",

volume = "26",

pages = "737–747",

journal = "Nature immunology",

issn = "1529-2908",

publisher = "Nature Research",

number = "5",

}

Keramati, F, Leijte, GP, Bruse, N, Grondman, I, Habibi, E, Ruiz-Moreno, C, Megchelenbrink, W, Peters van Ton, AM, Heesakkers, H, Bremmers, ME, van Grinsven, E, Tesselaar, K, van Staveren, S, van der Velden, WJ, Preijers, FW, Te Pas, B, van de Loop, R, Gerretsen, J, Netea, MG, Stunnenberg, HG, Pickkers, P & Kox, M 2025, 'Systemic inflammation impairs myelopoiesis and interferon type I responses in humans', Nature immunology, vol. 26, no. 5, e1001304, pp. 737–747. https://doi.org/10.1038/s41590-025-02136-4

TY - JOUR

T1 - Systemic inflammation impairs myelopoiesis and interferon type I responses in humans

AU - Keramati, Farid

AU - Leijte, Guus P

AU - Bruse, Niklas

AU - Grondman, Inge

AU - Habibi, Ehsan

AU - Ruiz-Moreno, Cristian

AU - Megchelenbrink, Wout

AU - Peters van Ton, Annemieke M

AU - Heesakkers, Hidde

AU - Bremmers, Manita E

AU - van Grinsven, Erinke

AU - Tesselaar, Kiki

AU - van Staveren, Selma

AU - van der Velden, Walter J

AU - Preijers, Frank W

AU - Te Pas, Brigit

AU - van de Loop, Raoul

AU - Gerretsen, Jelle

AU - Netea, Mihai G

AU - Stunnenberg, Hendrik G

AU - Pickkers, Peter

AU - Kox, Matthijs

PY - 2025

Y1 - 2025

N2 - Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.

AB - Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.

U2 - 10.1038/s41590-025-02136-4

DO - 10.1038/s41590-025-02136-4

M3 - Article

C2 - 40251340

SN - 1529-2908

VL - 26

SP - 737

EP - 747

JO - Nature immunology

JF - Nature immunology

IS - 5

M1 - e1001304

ER -

Systemic inflammation impairs myelopoiesis and interferon type I responses in humans

Abstract

Access to Document

Fingerprint

Cite this