Link to the original paper in Nature Immunology
Patients in intensive care are well documented to suffer severe immunosuppression at the time of sepsis; these patients tend to have persistent immunosuppression leading to secondary infections. The pathobiology behind this is less well studied- a gap the Nature Immunology paper addressed. Their findings reveal a compelling narrative:
Stage 1. The First Assault (Hyperinflammation):
-Healthy volunteers received intravenous LPS (2 ng/kg), inducing acute hyperinflammation. This was confirmed by clinical symptoms (fever, tachycardia) and increased circulating cytokines (TNF, IL-10, IL-6) up to 8 hours post-LPS.
-Single-cell RNA sequencing (scRNA-seq) of blood and bone marrow leukocytes identified a distinct inflammatory CD163+SLC39A8+CALR+ monocyte-like subset ("infMono") at 4 hours post-LPS.
-InfMonos showed increased pro-monocyte gene expression (e.g., RETN, ALOXSAP) and reduced mature monocyte markers (MHC-II genes). This indicated new, immature monocytes emerging in bone marrow and peripheral blood.
-Non-negative matrix factorization (NMF) defined an infMono-specific gene program (inflammatory, heat shock, IFN response, immature pro-monocyte genes).
-A distinct IFN-I responsive gene program (e.g., MXI, IRF1, ISG15) was induced in T cells and NK cells, termed inflammatory T cells (Tinf cells).
Crucially, these infMono and Tinf cell gene programs were significantly enriched in early bacterial sepsis and severe COVID-19 patients, respectively, highlighting clinical relevance.
Stage 2. The Lull and Lingering Weakness (Immunosuppression):
-Seven days post-LPS, the late immunosuppressive phase featured diminished IFN-responsive gene expression in monocytes and impaired myelopoiesis. This significantly reduced immune reactions, encompassing cytokine generation, to a subsequent LPS challenge.
-Impaired monocyte maturation, particularly loss of intermediate (iMonos) and nonclassical (ncMonos) monocytes, mirrored late-phase sepsis and COVID-19 patients. Critically, IFN-I signaling was significantly impaired.
Stage 3. A Glimmer of Hope (Therapeutic Potential): IFN-beta (IFNß) treatment restored type-I IFN responses and proinflammatory cytokine production (TNF, IL-6) in previously immunosuppressed monocytes ex vivo. IFNß also induced classical monocyte maturation towards iMonos in vitro, suggesting a potential therapy for reversing immunosuppression.
So What? Interferon therapy may help reduce the duration of immunosuppression following sepsis or other severe inflammatory insults by restoring the 'cytokine homeostasis'.
https://lnkd.in/gx5cUdca