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<p>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 <i>CD163</i><sup>+</sup><i>SLC39A8</i><sup>+</sup><i>CALR</i><sup>+</sup> 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.</p>

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Systemic inflammation impairs myelopoiesis and interferon type I responses in humans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月18日

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  • 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

摘要

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.