J Leukoc Biol. 2025 Jun 4;117(6):qiaf091. doi: 10.1093/jleuko/qiaf091.
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.
PMID:40590483 | DOI:10.1093/jleuko/qiaf091