FOLR3+neutrophils contribute to sepsis by exacerbating hyper-inflammation.

Sepsis severity is associated with sustained neutrophilia, yet the underlying heterogeneity remains unclear. By integrating single-cell and bulk RNA-seq of septic peripheral blood, we uncovered five neutrophils clusters. FOLR3+neutrophils were the predominant and terminally differentiated subgroup, which displayed hyper-inflammatory signatures and low HLA expression, especially in non-survivors of sepsis. Cell-chat analysis also showed these neutrophils could promote sepsis progression by recruiting platelet via RETN-CAP1 and NAMPT-ITGB1 axes. External validation found that higher FOLR3+neutrophils were associated with 28-day mortality of sepsis. Transcription-factor and pseudotime analyses identified HIF-1A as the key driver of FOLR3+neutrophils specification. In vitro experiments validated that FOLR3 expression and HIF-1A were also found to be higher in sepsis. Over-expression or knockout of HIF-1A in patient and mouse neutrophils confirmed direct control of HIF-1A on secretion of IL-1β, TNF-α, IL-8 and IL-6. In conclusion, FOLR3+neutrophils contribute to sepsis prognosis by exacerbating hyper-inflammation and FOLR3 may serve as a new promising prognostic biomarker for sepsis.