Norepinephrine-driven neutrophilic inflammation accelerates ulcerative colitis progression

The role of the sympathetic neurotransmitter norepinephrine (NE) in ulcerative colitis (UC) remains controversial. We aimed to elucidate NE's precise mechanisms in UC, focusing on colonic metabolism, diagnostic potential, and local immune interactions.

Colonic biopsies from active UC patients and DSS-colitis mice were profiled. Neurotransmitter levels, including NE, were quantified by targeted metabolomics. An NE-pathway diagnostic model was constructed from bulk RNA-seq data using machine learning. In vivo, NE was administered via enema or intraperitoneal injection at graded concentrations to assess its pro-inflammatory effects. Immune cells were characterized by flow cytometry, scRNA-seq and spatial transcriptomics. In vitro, NE's effects on neutrophils were verified with receptor inhibitors. Clinical relevance was evaluated using pre-treatment mucosal RNA-seq and therapeutic response data.

UC patients and DSS mice exhibited elevated local NE levels, influenced by increased biosynthesis and reduced degradation. A machine learning classifier based on NE-pathway genes achieved high accuracy (AUC > 0.9) for UC detection. Experimentally, at low concentrations, NE enemas-but not intraperitoneal administration-aggravated acute colitis in DSS mice via colonic neutrophils. Mechanistically, NE exacerbated colitis by enhancing the pro-inflammatory phenotype of neutrophils through adrenergic receptor β2 (Adrb2)-mediated elevation of intracellular ROS. Subsequently, Adrb2⁺ neutrophils drove inflammatory crosstalk via TNF-TNFR1/2 signaling. Clinically, high ADRB2⁺ neutrophil infiltration predicted favorable responses to infliximab.

This study identifies localized NE accumulation as a neutrophil-dependent driver of UC progression via Adrb2-neutrophil-TNF inflammatory cascade, providing a mechanistic rationale that may help guide biologic agent selection and support strategies with selective ADRB2 antagonists in UC treatment.