Journal Article

Systemic inflammation impairs myelopoiesis and interferon type I responses in humans

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

2025

Overview

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. Stunnenberg et al. use a model of lipopolysaccharide injection in humans to characterize the transcriptomic landscape of bone marrow and blood immune cells during the hyperinflammatory and immunosuppressed phases of systemic inflammation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/232 / 631/250/255 / 631/250/262/2106/2108 / Biomedical and Life Sciences / Biomedicine / Bone marrow / CD163 antigen / Coronaviruses / COVID-19 - immunology / Cytokines - metabolism / Female / Humans / Immune response / Immunology / Immunosuppression / Infectious Diseases / Inflammation / Inflammation - immunology / Interferon Type I - immunology / Interferon Type I - metabolism / Lipopolysaccharides / Lipopolysaccharides - immunology / Male / Monocytes / Monocytes - immunology / Monocytes - metabolism / Myelopoiesis / Myelopoiesis - genetics / Myelopoiesis - immunology / Sepsis / Sepsis - immunology / Single-Cell Analysis / Transcriptomics / β-Interferon