Control of neutrophil effector function by the actin-regulatory protein coronin 1a
SHAVERSKYI A. 1, LEE K. 1, FÖGER N. 1
1 Inflammation Research Group, Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
Neutrophils are crucial innate immunity cells that play a fundamental role in antimicrobial response and in?ammation-related tissue damage. To combat invading pathogens, neutrophils employ an array of powerful effector mechanisms: phagocytosis, release of antimicrobial compounds from granules, and the generation of reactive oxygen species (ROS) that, jointly, kill ingested microbes. Neutrophil effector functions involve dynamic reorganization of the actin cytoskeleton. However, the functional links between neutrophil effector function and actin cytoskeletal regulation are still poorly understood.
In this project, we explored the role of the evolutionary highly conserved actin-regulatory protein coronin 1a in neutrophil effector function.
Employing neutrophils from coronin 1a-deficient mice, we analyzed different neutrophil-mediated defense mechanisms that were induced by various stimuli. Additional experiments were aimed at uncovering the mechanism underlying coronin 1a action in neutrophils.
Analysis of neutrophils from coronin 1a-deficient mice indicated normal neutrophil development in the bone marrow, but revealed defects in effector function of mature neutrophils. Coronin 1a-null neutrophils exhibited impaired ROS generation and reduced release of all neutrophil granule types in response to a wide range of stimuli. Impaired defense function of coronin 1a-deficient neutrophils correlated with increased F-actin levels and reduced Rac activation, which is consistent with an actin-regulatory role of coronin 1a. Mechanistic studies showed that pharmacological modulation of F-actin stability and Rac activation status indeed alter ROS production and degranulation. These data indicate that coronin 1a is critically required for cytoskeletal regulation via association with Rac and Arp2/3 complex that, consequently, mediates normal granule release and ROS generation.
In summary, our data revealed impaired ROS production and decreased neutrophil degranulation that are associated with alterations in actin cytoskeletal organization in coronin 1a-deficient neutrophils. These findings indicate a pivotal involvement of coronin 1a and, in turn, the actin cytoskeleton in the coordination of neutrophil-mediated defense mechanisms.