Coronin-1 Is Associated with Neutrophil Survival and Is Cleaved during Apoptosis: Potential Implication in Neutrophils from Cystic Fibrosis Patients

Abstract

Because neutrophil apoptosis plays a key role in resolving inflammation, identification of proteins regulating neutrophil survival should provide new strategies to modulate inflammation. Using a proteomic approach, coronin-1 was identified as a cytosolic protein cleaved during neutrophil apoptosis. Coronin-1 is an actin-binding protein that can associate with phagosomes and NADPH oxidase, but its involvement in apoptosis was currently unknown. In coronin-1-transfected PLB985 cells, coronin-1 overexpression did not modify the kinetics of granulocyte differentiation as assessed by CD11b labeling. Concerning apoptosis, increased coronin-1 expression in dimethylformamide-differentiated PLB985 significantly decreased gliotoxin-induced mitochondrial depolarization as compared with controls. Likewise, coronin-1 significantly decreased TRAIL-induced apoptosis with less mitochondrial depolarization, caspase-3 and caspase-9 activities, but not caspase-8 or Bid truncation suggesting that coronin-1 interfered with mitochondria-related events. To validate the prosurvival role of coronin-1 in a pathophysiological condition involving neutrophil-dominated inflammation, neutrophils from cystic fibrosis (CF) patients were studied. Circulating neutrophils from CF patients had more coronin-1 expression assessed by immunoblotting or proteomic analysis of cytosolic proteins. This was associated with a lower apoptosis rate than those from controls evidenced by delayed phosphatidylserine externalization and mitochondria depolarization. In addition, inflammatory neutrophils from CF patients lungs showed an intense coronin-1 immunolabeling. We concluded that coronin-1 could constitute a potential target in resolving inflammation.

Contribution of Neutrophils to Acute Lung Injury

“…Moreover, the serine proteases are also involved in noninfectious inflammatory disease (129,137). In humans, proteinase 3 is elucidated as the main target antigen of neutrophil cytoplasm autoantibodies (c-ANCA) in Wegener granulomatosis, a vasculitis which affects lungs, kidneys and the skin (138). Proteinase 3 interacts with specific intracellular protein substrates during proliferation and apoptosis (137).…”

A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy

“…17,18 Observations of neutrophildominated airway inflammation in children with CF, 19,20 delayed cell apoptosis in heterozygote individuals, 21,22 and impaired CFTRdependent vacuolar Cl 2 transport and microbial killing 7,23-25 support an innate defect rather than inflammatory cell reprogramming in the control of neutrophil functionality in CF; yet further studies are required to corroborate this theory.…”

Proof of Principle for a T Lymphocyte Intrinsic Function of Coronin 1A

“…able for the functionality of neutrophils, mast cells, dendritic cells, and B cells, even though some controversy exists concerning the role of Coro1A in neutrophils and mast cells (5)(6)(7)(8)(9)(10).…”