A novel physiological pathway in the regulation of neutrophil activation

Neutrophils are key participants in the innate immune system and the first responders to inflammatory stimuli. This rapid response of neutrophils is achieved by their polarization and migration towards inflammatory mediators, however the mechanisms that regulate these changes are only partly understood. Recent studies support a role for calpain I in regulating neutrophil polarization and directional migration to chemotactic stimuli. Our study reveals a previously unknown function for acute phase protein, α1-proteinase inhibitor or α1-antitrypsin (AAT) to inhibit calpain I and to activate the Rho GTPases, Rac and Cdc42, and induces phosphorylation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase (ERK1/2), p38, and phosphatidylinositol 3-kinase (PI3K)/Akt which is also related to rapid neutrophil polarization and random migration. Remarkably, time-dependent F-actin reorganization during AAT-induced neutrophil polarization is associated with the intracellular entry of AAT and the formation of lipid droplets which partially co-localize with AAT. Lipid droplets appear to be heterogeneous in size and distribution, initially occurring as smaller droplets within the cell body and later accumulating as larger lipid bodies at the tail (uropod) of the fully polarized neutrophil. Notably, AAT also significantly decreases neutrophil adhesion and increases life span. Our findings provide the first demonstration that an acute phase protein AAT- regulates neutrophil activation and encourage future research of physiological relevance and/or pathological importance of its diverse functions.