Multimodal Imaging Reveals Rapid Catecholamine Uptake and Release by Neutrophils

ABSTRACT Neutrophils are key inflammatory effector cells and rapidly integrate chemical signals during inflammation. They have long been suspected to use catecholamines (CAs) as immunoregulatory signals, but direct evidence for CA handling in these cells has been lacking due to the absence of suitable real‐time detection tools. Here, we combine fluorescent false neurotransmitters (FFNs), near‐infrared fluorescent single‐walled carbon nanotube (SWCNT)‐based catecholamine nanosensors, dual‐color Ca 2 + imaging, and transcriptomics to resolve neutrophil CA dynamics with high spatiotemporal precision. Using FFNs, we demonstrate VMAT2‐dependent vesicular uptake of catecholamines within seconds as well as CA transfer between cells. Serotonin, LPS, and activated platelets trigger calcium (Ca 2+ ) signaling and subsequent fast transient release of CAs from neutrophils, which we directly visualize in real time using SWCNT‐based nanosensors. In human experimental endotoxemia, longitudinal transcriptomics reveal coordinated regulation of monoaminergic receptors, synthesis machinery, and transporters, suggesting adaptive tuning of neutrophils to inflammatory CA exposure. CAs suppress NET formation but enhance thrombin‐induced platelet aggregation, and serotonin‐dependent platelet–neutrophil interactions evoke CA release, establishing a paracrine feedback loop linking inflammation and coagulation. Our integrated imaging and sensing workflow provides direct evidence for rapid vesicular catecholamine communication in human neutrophils and uncovers previously unrecognized mechanistic parallels between neurons and neutrophils. It offers a broadly applicable platform to interrogate monoamine signaling in immune cells.