# Mechanism of GSDMD in the Pathogenesis of Pasteurella multocida PmCQ2

## TL;DR

This study shows how the pathogen PmCQ2 causes lung damage through pyroptosis, a type of cell death, and highlights GSDMD as a potential therapeutic target.

## Contribution

The study is the first to demonstrate dual signaling pathways of GSDMD-dependent pyroptosis in PmCQ2-induced lung injury.

## Key findings

- PmCQ2 induces macrophage pyroptosis via GSDMD cleavage, confirmed by LDH release and TEM.
- NLRP3 and caspase-11 inhibition reduces GSDMD activation and pyroptosis in PmCQ2 infection.
- GSDMD knockout mice show reduced lung injury and inflammation after PmCQ2 challenge.

## Abstract

Pasteurella multocida serotype A (PmCQ2), a Gram‐negative zoonotic pathogen, causes severe respiratory disease in a variety of domestic and wild animals, leading to high morbidity and mortality and substantial agricultural economic losses. Pyroptosis, a gasdermin‐mediated programmed cell death mechanism, facilitates pathogen clearance but exacerbates tissue damage through inflammatory cytokine release. While our prior work established PmCQ2‐driven NOD‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation, the role of pyroptosis in pulmonary pathology during infection remains unresolved. Here, we demonstrate that PmCQ2 induces macrophage pyroptosis via gasdermin D (GSDMD) cleavage, evidenced by lactate dehydrogenase (LDH) release, membrane pore formation under transmission electron microscopy (TEM), and proteolytic generation of GSDMD‐N termini. Pharmacological inhibition of NLRP3 (MCC950) and genetic ablation of caspase‐11 significantly attenuated GSDMD activation, IL‐1β secretion, and pyroptotic cell death, implicating both canonical (NLRP3/caspase‐1) and noncanonical (caspase‐11) pathways. Crucially, GSDMD knockout mice exhibited markedly reduced lung injury, evidenced by diminished inflammatory infiltration and preserved alveolar architecture, compared to wild‐type (WT) counterparts following PmCQ2 challenge. This study provides the first evidence that PmCQ2 triggers GSDMD‐dependent pyroptosis through dual signaling axes, directly linking this inflammatory cell death pathway to pathogen‐induced pulmonary damage. Our findings position GSDMD as a central therapeutic target to mitigate tissue injury during P. multocida infection, offering a framework for novel interventions that balance antimicrobial defense and inflammation control in zoonotic pathogens.