A GROUNDBREAKING new study has shed light on the complex immune dynamics underlying systemic inflammation, a key contributor to nearly 20% of global deaths. Conditions such as sepsis, COVID-19, and other severe infections often trigger a two-stage immune response: an acute hyperinflammatory burst, commonly known as a “cytokine storm”, followed by a late immunosuppressive phase that leaves patients vulnerable to secondary infections and long-term complications.
Researchers employed an advanced human in vivo model known as experimental endotoxemia, in which healthy volunteers are administered bacterial lipopolysaccharide (LPS) to simulate systemic inflammation. This approach allowed for precise monitoring of the immune response over time, avoiding the common limitations of traditional mouse models that often fail to replicate human inflammatory processes accurately.
By integrating cutting-edge single-cell RNA sequencing (scRNA-seq) with cellular functional assays, the team meticulously profiled immune responses in blood and bone marrow samples across both phases of inflammation. Their findings revealed distinct, cell-specific gene expression programmes, particularly in monocytes and T cells, which were consistently activated during the acute inflammatory phase. These transcriptional patterns were also observed in patient cohorts suffering from early-stage sepsis and COVID-19, highlighting the clinical relevance of the model.
Crucially, during the immunosuppressive phase, researchers identified a marked decline in monocyte function and maturation, alongside weakened type I interferon (IFN-I) signalling – an essential component of antiviral and antibacterial defence. Notably, this suppressed state could be reversed through treatment with interferon-beta (IFNβ), opening up potential therapeutic avenues to mitigate long-term immune dysfunction in critically ill patients.
This study not only enhances our understanding of systemic inflammation’s biphasic nature but also highlights the importance of cell-specific analysis in identifying viable targets for intervention. As healthcare systems continue to grapple with the burden of inflammation-driven diseases, these insights could pave the way for more precise and effective treatments.
Reference
Keramati F, Leijte GP, Bruse N, et al. Systemic inflammation impairs myelopoiesis and interferon type I responses in humans. Nat Immunol. Published online April 18, 2025. doi:10.1038/s41590-025-02136-4
