Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution 2218223

Abstract

Abstract Introduction Neutrophils, the most abundant white blood cells and first responders to immune challenges, have long been considered short-lived with unclear evolutionary purpose. We discovered Large Aging Neutrophil-Derived Vesicles (LAND-Vs), generated during neutrophil aging independent of cell death, that modulate immunity by targeting complement activation. This represents the first example of typically pro-inflammatory neutrophils actively dampening inflammation to restore homeostasis. Methods Using novel live imaging, spectral flow cytometry with unbiased clustering, and imaging flow—based machine learning we systematically characterized LAND-Vs, defining their temporal regulation, heterogeneity, pathophysiological roles, and biogenesis. Results Live imaging of neutrophil aging revealed that LAND-Vs are actively produced independent of cell death. These vesicles exert potent anti-inflammatory effects through surface CD55, which inhibits complement C3 convertase, thereby limiting inflammation and tissue damage. In inflamed lungs, LAND-Vs persisted beyond neutrophil decline and complement activity, supported by “do not eat me” signals that prevented macrophage clearance and sustained complement deactivation. Mechanistically, asymmetric CD55 polarization during neutrophil aging drove lipid raft—dependent formation of CD55+ LAND-Vs. Clinically, circulating CD55+ LAND-Vs inversely correlated with COVID-19 severity. Conclusion This work uncovers a previously unrecognized neutrophil function: an active anti-inflammatory role mediated by LAND-V production as a programmed feature of aging rather than cell death. LAND-Vs represent a distinct class of large extracellular vesicles. Their discovery redefines neutrophil aging as an active, biologically purposeful process, extending function beyond cell death. This paradigm shift opens new directions in immunology and translational research with important clinical implications in inflammatory and infectious diseases. Funding Source NIH Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)