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 Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter JFM van der Velden, Frank Preijers, Brigit M. te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G. Netea, Hendrik G. Stunnenberg, Peter Pickkers, Matthijs Kox
Abstract
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.