IL-18-associated basophil and mast cell activation in sepsis.

Abstract

Background: The contributions of basophils and mast cells to sepsis immunopathology remains poorly understood. Interleukin-18 (IL-18) has established roles in innate immune activation, but its relationships with basophil and mast cell activation during sepsis have not been fully defined.

Methods: We investigated expression of IL-18Rα and activation marker CD63 on blood basophils of patients with sepsis using flow cytometry and RNA-sequencing. Sepsis mouse model and human cell lines were used to assess the effect of IL-18 on basophil and mast cell activation.

Results: Close correlations between elevated plasma IL-18 level and increased CD63, IL-18Rα and IL-18Rβ protein expression on basophils of patients with sepsis were observed. Transcriptomic analysis revealed extensive reprogramming of septic basophils, including upregulation of CD63 and IL18RAP, together with enrichment of pathways related to ribosome biogenesis, mitochondrial translation, oxidative phosphorylation, proteasome, DNA replication and cell cycle. Furthermore, we observed increased expression of CD63 and IL-18Rα on basophils and mast cells in septic mice, and IL-18 upregulated their expression and mast cell accumulation in both healthy and septic mice. Additionally, elevated plasma and peritoneal levels of IL-18, IL-5, CCL2 and tryptase were observed in septic mice. In vitro experiments demonstrated that both IL-18 and plasma from patients with sepsis induced upregulation of CD63 and IL-18Rα on KU812 and HMC-1 cell lines.

Conclusions: Collectively, our findings suggest that IL-18-associated basophil and mast cell activation may participate in sepsis-related inflammation.