Neutrophil inflammasome mechanisms in host defense and inflammatory responses

The National Institute of Allergy and Infectious Diseases awarded the University of Arkansas for Medical Sciences $249,856 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate neutrophil inflammasome mechanisms in host defense and inflammatory responses.

The research examines how neutrophils regulate pyroptosis—a form of lytic cell death triggered by inflammasomes—during bacterial infections and inflammatory conditions including sepsis and autoinflammatory diseases. The investigator will assess how neutrophil-derived reactive oxygen species modulate gasdermin D post-translational modifications during phagocytic and non-phagocytic bacterial infections, examine calcium-mediated membrane repair mechanisms that limit inflammasome-driven pyroptosis, and evaluate the role of neutrophil-intrinsic inflammasomes in autoinflammatory pathology using a caspase-1-active mouse model. Current understanding of pyroptosis regulation remains unclear, limiting development of therapies for pathogenic infections and inflammatory disorders, particularly in immunocompromised patients.

Performance occurs in Little Rock, Arkansas. The award period runs September 1, 2026, through August 31, 2031.

Abstract

Inflammasomes are vital innate immune complexes that detect microbial threats and stress. They activate inflammatory caspase-1, which cleaves gsdmd and triggers pyroptosis, a form of lytic cell death, while releasing pro-inflammatory cytokines such as IL-1Β and IL-18. Neutrophils, the most abundant type of leukocyte, fight bacterial infections through mechanisms like phagocytosis, antimicrobial release, and the formation of neutrophil extracellular traps (NETS). Unlike macrophages, however, neutrophils resist pyroptosis driven by caspase-1. Our research indicates that the mode of infection influences pyroptosis in neutrophils: cytosolic bacterial effectors can induce pyroptosis and enhance net formation, leading to improved extracellular bacterial clearance. In contrast, phagocytosing bacteria suppress pyroptosis, which increases susceptibility to intracellular infections. This points to a tight regulation of gsdmd, yet the underlying mechanisms and their roles in infection versus inflammatory conditions (such as sepsis and autoinflammatory diseases) remain unclear. This lack of understanding limits the development of therapies for pathogenic infections and inflammatory disorders, particularly in immunocompromised patients. We hypothesize that neutrophils regulate pyroptosis through reactive oxygen species (ROS) and calcium dynamics, with dysregulated pyroptosis contributing to inflammatory pathologies. To explore this, we will investigate how neutrophil-derived ROS modulates gsdmd post- translational modifications during phagocytic and non-phagocytic infections. Additionally, we will examine how calcium-mediated membrane repair limits inflammasome-driven pyroptosis and how low calcium levels (HYPOCALCEMIA) worsen inflammatory conditions. Finally, we will assess the role of neutrophil-intrinsic inflammasomes in autoinflammatory pathology using a caspase-1-active mouse model. This research aims to clarify the regulation of pyroptosis in neutrophils, revealing novel therapeutic targets for infections, sepsis, and autoinflammatory diseases. This work addresses critical needs in immunocompromised populations and seeks to improve clinical outcomes.