Dataset Information

Large Aging Neutrophil-Derived Vesicles (LAND-Vs) Perpetuate Host Anti-Inflammatory Response to Facilitate Inflammation Resolution

ABSTRACT: Precise regulation of the duration and extent of inflammation is crucial for balancing pathogen elimination and preventing tissue damage. The mechanisms underlying inflammation resolution are not yet fully understood. Here, we reveal that neutrophils, typically known for their pro-inflammatory role and pathogen clearance capabilities, can paradoxically aid in resolving inflammation by actively producing anti-inflammatory vesicles. Large aging neutrophil-derived vesicles (LAND-Vs) emerged in inflamed lungs during bacterial pneumonia. These vesicles, protected from efferocytotic clearance by phagocytes due to surface CD47, CD24, or CD31, accumulated in the resolution phase of inflammation and persisted at the site long after neutrophil recruitment subsided. CD55 on LAND-Vs exerted a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase and suppressing complement activity, thereby reducing neutrophil recruitment and tissue damage. A combination of neutrophil-specific CD55 knockout and adoptive transfer experiments demonstrated that LANDs were not only essential but also sufficient for efficient inflammation resolution. CD55+ LAND-Vs originated in lipid rafts, where CD55 accumulated asymmetrically during neutrophil aging, and subsequently formed through RhoA-dependent budding. Intriguingly, the number of CD55+ LAND-Vs in the peripheral blood of severe COVID-19 patients was markedly lower than that in healthy individuals or patients with milder cases of COVID-19, indicating that LAND-Vs might contribute to mitigating pathologies observed in severe COVID-19 patients. In conclusion, LAND-Vs, a unique structure originating from aging neutrophils, emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a promising therapeutic target for inflammatory and infectious diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Neutrophil

SUBMITTER: Alan Hsu

LAB HEAD: Hongbo Luo

PROVIDER: PXD048609 | Pride | 2026-03-23

REPOSITORIES: Pride

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Publications

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

Hsu Alan Y AY Huang Qingxiang Q Pi Xiong X Fu Jianing J Raghunathan Krishnan K Ghimire Laxman L Balasubramanian Arumugam A Xie Xuemei X Yu Hongbo H Loison Fabien F Haridas Viraga V Zha Jiali J Liu Fei F Park Shin-Young SY Bagale Kamal K Ren Qian Q Fan Yuping Y Zheng Yi Y Cancelas Jose A JA Chai Li L Stowell Sean R SR Chen Kanchao K Xu Rong R Wang Xiaoxue X Xu Yuanfu Y Zhang Lianghui L Cheng Tao T Ma Fengxia F Thiagarajah Jay R JR Wu Hao H Feng Sizhou S Luo Hongbo R HR

Cell 20250211 6

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) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from effe ...[more]

PMID: 39938514

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Project description:Dunster2014 - WBC Interactions (Model1) This is a sub-model of a three-step inflammatory response modelling study. The model includes distinct populations of white blood cells namely, macrophages and active and apoptotic neutrophil populations. Neutrophil apoptosis rate is predicted to be crucial for the qualitative nature of the system. This model is described in the article: The resolution of inflammation: a mathematical model of neutrophil and macrophage interactions. Dunster JL, Byrne HM, King JR. Bull. Math. Biol. 2014 Aug; 76(8): 1953-1980 Abstract: There is growing interest in inflammation due to its involvement in many diverse medical conditions, including Alzheimer's disease, cancer, arthritis and asthma. The traditional view that resolution of inflammation is a passive process is now being superceded by an alternative hypothesis whereby its resolution is an active, anti-inflammatory process that can be manipulated therapeutically. This shift in mindset has stimulated a resurgence of interest in the biological mechanisms by which inflammation resolves. The anti-inflammatory processes central to the resolution of inflammation revolve around macrophages and are closely related to pro-inflammatory processes mediated by neutrophils and their ability to damage healthy tissue. We develop a spatially averaged model of inflammation centring on its resolution, accounting for populations of neutrophils and macrophages and incorporating both pro- and anti-inflammatory processes. Our ordinary differential equation model exhibits two outcomes that we relate to healthy and unhealthy states. We use bifurcation analysis to investigate how variation in the system parameters affects its outcome. We find that therapeutic manipulation of the rate of macrophage phagocytosis can aid in resolving inflammation but success is critically dependent on the rate of neutrophil apoptosis. Indeed our model predicts that an effective treatment protocol would take a dual approach, targeting macrophage phagocytosis alongside neutrophil apoptosis. This model is hosted on BioModels Database and identified by: BIOMD0000000616. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background: Neutrophil function declines with age, but little is known about the changes in neutrophil metabolism that take place in older people and people with frailty. We used 1H-NMR spectroscopy to investigate the metabolic profiles of neutrophils from healthy younger (HY) and older (HO) people and older people with frailty (FR), to identify metabolites and metabolic pathways altered with healthy ageing and ageing with frailty. We also compared FR metabolites to rheumatoid arthritis (RA) neutrophils to identify markers of inflammation in FR neutrophils. Methods: 1H-NMR spectroscopy was performed on polar and lipid metabolites extracted from blood neutrophils. Polar metabolites were annotated using Chenomx prior to univariate (ANOVA, Tukey’s adjusted p-value<0.05) and supervised (partial least square discriminant analysis, PLS-DA) multivariate analyses in R (v4.4.1). Lipid metabolites were analysed as spectral bins. Metabolite enrichment analysis was performed using Metaboanalyst (v6) against the small molecule pathway database (SMPDB).  Results: ANOVA identified 17 polar metabolites significantly different across the participant groups (adj. p<0.05). Three polar metabolites were significantly different in FR vs HO neutrophils, with NADP being higher in FR and lysine and choline being lower. NADP was uniquely elevated in FR compared to HO, HY and RA neutrophils. Seven metabolites were significantly different between HO and HY neutrophils, and only 2 metabolites were different between FR and RA neutrophils, identifying underlying similarities between FR and RA that may be driven by inflammation. Four lipid peaks were significantly different between FR and HY neutrophils. These were attributed to total cholesterol and arachidonic acid. Conclusions: This is the first study of polar and lipid metabolism in neutrophils from people with frailty. Our results provide evidence that metabolic signalling pathways involved in neutrophil activation, oxidative stress and lipid metabolism are altered during healthy ageing and ageing with frailty, and we identify NADP as a unique biomarker of altered neutrophil function in people with frailty.

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Dataset Information

Large Aging Neutrophil-Derived Vesicles (LAND-Vs) Perpetuate Host Anti-Inflammatory Response to Facilitate Inflammation Resolution

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Publications

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

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