FOLR3+neutrophils contribute to sepsis by exacerbating hyper-inflammation

Area of Science:

• Immunology
• Genomics
• Critical Care Medicine

Background:

• Sepsis severity correlates with persistent neutrophilia, but neutrophil heterogeneity is not well understood.
• Understanding neutrophil subtypes is crucial for predicting sepsis progression and patient outcomes.

Purpose of the Study:

• To investigate neutrophil heterogeneity in sepsis using integrated single-cell and bulk RNA sequencing.
• To identify specific neutrophil subsets associated with sepsis severity and mortality.
• To elucidate the molecular mechanisms driving the identified neutrophil populations.

Main Methods:

• Integrated single-cell and bulk RNA sequencing of peripheral blood from septic patients.
• Cell-chat analysis to predict intercellular communication.
• Transcription-factor and pseudotime analyses to identify key regulatory factors.
• In vitro experiments with patient and mouse neutrophils to validate findings.

Main Results:

• Five distinct neutrophil clusters were identified, with FOLR3+neutrophils being predominant and terminally differentiated.
• FOLR3+neutrophils exhibited hyper-inflammatory signatures, low HLA expression, and were associated with non-survival.
• These neutrophils promote sepsis progression by recruiting platelets via specific signaling axes (RETN-CAP1 and NAMPT-ITGB1).
• Higher FOLR3+neutrophil counts correlated with increased 28-day mortality in sepsis patients.
• Hypoxia-inducible factor 1-alpha (HIF-1A) was identified as the key transcription factor driving FOLR3+neutrophil specification.
• HIF-1A directly controls the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8, IL-6) by neutrophils.

Conclusions:

• FOLR3+neutrophils exacerbate hyper-inflammation in sepsis, contributing to poor prognosis.
• FOLR3+neutrophils represent a distinct, terminally differentiated subset with significant implications for sepsis severity.
• FOLR3 emerges as a potential novel prognostic biomarker for sepsis, warranting further clinical investigation.