ArticleJournal of leukocyte biology2025
Alpha-1 antitrypsin modulates neutrophil phenotype and function: implications for inflammatory regulation.
Article in Journal of leukocyte biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
5 citing papers in PubMed.
- Alpha-1 antitrypsin deficiency associated with increased risk of venous thromboembolism: a nationwide cohort study in Denmark.Research and practice in thrombosis and haemostasis · 2026Article
- Alpha-1 antitrypsin-glucocorticoid receptor axis: a new pathway in immune modulation.Molecular medicine (Cambridge, Mass.) · 2026Article
- Identification and validation of platelet activation-related signatures in ulcerative colitis: a study based on machine learning and single-cell transcriptomic analysis.Frontiers in immunology · 2026Article
- Neutrophil Plasticity in Airway Disease: Balancing Damage and Repair.Journal of innate immunity · 2026Review
- Neutrophil-derived extracellular vesicles in the plasma of alpha-1 antitrypsin deficient individuals reveal pro-inflammatory metabolic and transcriptomic signatures.Extracellular vesicle · 2025Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Alpha-1 antitrypsin, the most abundant protease inhibitor within the plasma, plays a crucial role in regulating neutrophils' function during inflammation. Alpha-1 antitrypsin deficiency is associated with excessive neutrophilic inflammation, yet the mechanisms underlying alpha-1 antitrypsin's role in neutrophil trafficking remain poorly understood. Here, we demonstrate alpha-1 antitrypsin is essential for maintaining neutrophil polarity, directional migration, and tissue infiltration during inflammation. Using alpha-1 antitrypsin-knockout mice, we found these mice present increased numbers of neutrophils in the bone marrow, impaired mobilization, and reduced liver neutrophil infiltration following lipopolysaccharide-induced systemic inflammation. Flow cytometry and immunohistochemistry revealed alpha-1 antitrypsin-knockout neutrophils had lower CD44 expression and defective F-actin polarization leading to impaired chemotaxis. Importantly, low expression of CD44 prevented efficient adhesion and transmigration of alpha-1 antitrypsin-knockout neutrophils across liver sinusoidal endothelial cells. Furthermore, chemotaxis assays showed alpha-1 antitrypsin-knockout neutrophils in alpha-1 antitrypsin-deficient media displayed random motility and loss of directional migration toward fMLP (N-Formyl-Met-Leu-Phe), suggesting a critical role for alpha-1 antitrypsin in neutrophil trafficking. Additionally, plasma alpha-1 antitrypsin deficiency delayed neutrophils' rate of phagocytosis. Mechanistically, alpha-1 antitrypsin deficiency resulted in excessive ERK1/2 (Extracellular Signal-Regulated Kinase 1/2) activation in alpha-1 antitrypsin-knockout neutrophils, driving an interleukin-10-enriched environment while suppressing expression of CXCL1 (C-X-C Motif Chemokine Ligand 1) and CXCL10 (C-X-C Motif Chemokine Ligand 10), chemokines essential for neutrophil recruitment. Notably, exposure to wild-type plasma with sufficient alpha-1 antitrypsin restored ERK1/2 activation, CD44 expression, and chemokine levels in alpha-1 antitrypsin-knockout neutrophils, confirming the role of circulating alpha-1 antitrypsin in maintaining neutrophil function. These findings highlight alpha-1 antitrypsin as a key regulator of neutrophil trafficking, adhesion, and immune signaling, with implications for alpha-1 antitrypsin deficiency-related inflammatory disorders.
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Registered trials
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