Neutrophil pyroptosis mediates pathology of P. aeruginosa lung infection in the absence of the NADPH oxidase NOX2

Abstract

Nod-like receptor family, CARD domain-containing 4 (NLRC4) inflammasome activation is required for efficient clearance of intracellular pathogens through caspsase-1-dependent pyroptosis in macrophages. Although neutrophils have a critical role in protection from Pseudomonas aeruginosa infection, the mechanisms regulating inflammasome-mediated pyroptosis in neutrophils and its physiological role are largely unknown. We sought to determine the specific mechanisms regulating neutrophil pyroptosis in P. aeruginosa strain PAO1 (PAO1) lung infection and to identify the pathological role of this process. Nox2 models with reduced neutrophil antibacterial activity exhibited increased neutrophil pyroptosis, which was mediated by flagellin, a pathogenic PAO1 component. We also demonstrate that PAO1-induced pyroptosis depended on NLRC4 and Toll-like receptor 5 (TLR5) in neutrophils generated from Nlrc4 or Tlr5 mice. Our study reveals previously unknown mechanisms and physiological role of neutrophil pyroptosis during P. aeruginosa lung infection. Furthermore, our findings regarding neutrophil pyroptosis in the context of neutrophil dysfunction may explain the causes of acute and/or chronic infectious diseases discovered in immune-compromised patients.

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

“…Neutrophils can undergo pyroptosis in mice lacking the NADPH oxidase NOX2 infected with Pseudomonas aeruginosa, 114 suggesting that pyroptosis can be activated to compensate for deficiency of another major anti-microbial pathway.…”

“…Typhimurium infection and other inflammasome activators (113), indicating that neutrophils would be a suitable phagocytic cell type to clear residual bacteria in the tissue. Neutrophils can undergo pyroptosis in mice lacking the NADPH oxidase NOX2 infected with Pseudomonas aeruginosa (114), suggesting that pyroptosis can be activated to compensate for deficiency of another major antimicrobial pathway.…”

Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection

“…Even fully functional neutrophils, however, are frustrated in their ability to phagocytize and kill P. aeruginosa within biofilms [75]. This incapacity may have further consequences: experimentally impairing neutrophilic elimination of P. aeruginosa via knockout of the Nox2 NADPH oxidase resulted in flagellin-mediated neutrophil pyroptosis that was dependent on NLRC4 and TLR5 activity [76]. …”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…Epithelial cell induction of apoptosis is canonically regarded as a means through which the host can restrict pathogen replication in infected cells, without loss of membrane integrity and the secretion of DAMPs leading to hyper-inflammatory responses by the immune system (207). Many respiratory pathogens compromise pulmonary tolerance through the inhibition of apoptotic cell death and the upregulation of more inflammatory forms of cell death, such as necrosis, oncosis, or pyroptosis (208)(209)(210)(211). The hyper-inflammatory response to such forms of cell death is affected by immune cells sensing DAMPs.…”