Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution 9058

Abstract Description Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging neutrophil-derived vesicles (LAND-Vs) did not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They were protected from efferocytotic clearance by phagocytes due to surface “don’t eat-me” signals and accumulated in the resolution phase of inflammation. CD55 on LAND-Vs exerted a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55+ LAND-Vs originated in ordered lipid raft domains, where CD55 accumulated asymmetrically during neutrophil aging, and were subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases. Funding Sources This work was supported by National Institutes of Health grants 1R01AI142642, 1R01AI145274, 1R01AI141386, R01HL092020, and P01HL158688. Alan Hsu is supported by NIH training grant T32HL066987 and the Cotran-Gimbrone Research Award. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)