Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis

TLDR

Sepsis is a frequently fatal disease driven by an uncontrolled, harmful host response to infection, yet its underlying pathophysiology remains poorly understood. In a mouse model of abdominal sepsis, innate response activator B cells produce IL‑3, which stimulates Ly‑6C^high monocyte and neutrophil myelopoiesis and amplifies the cytokine storm. IL‑3 promotes sepsis‑induced inflammation, as IL‑3 deficiency protects mice and elevated plasma IL‑3 in humans predicts higher mortality, positioning IL‑3 as a key orchestrator of emergency myelopoiesis and a promising therapeutic target.

Abstract

Sepsis is a frequently fatal condition characterized by an uncontrolled and harmful host reaction to microbial infection. Despite the prevalence and severity of sepsis, we lack a fundamental grasp of its pathophysiology. Here we report that the cytokine interleukin-3 (IL-3) potentiates inflammation in sepsis. Using a mouse model of abdominal sepsis, we showed that innate response activator B cells produce IL-3, which induces myelopoiesis of Ly-6C(high) monocytes and neutrophils and fuels a cytokine storm. IL-3 deficiency protects mice against sepsis. In humans with sepsis, high plasma IL-3 levels are associated with high mortality even after adjusting for prognostic indicators. This study deepens our understanding of immune activation, identifies IL-3 as an orchestrator of emergency myelopoiesis, and reveals a new therapeutic target for treating sepsis.