Casp11 Deficiency Alters Subgingival Microbiota and Attenuates Periodontitis

Area of Science:

• Immunology
• Microbiology
• Oral Health

Background:

• Periodontitis (PD) is a major cause of adult tooth loss, with *Porphyromonas gingivalis* (*P.g*) as a key pathogen.
• Noncanonical pyroptosis, mediated by Caspase-11 (human Caspase-4/5), is implicated in PD, but its precise role remains unclear.
• Understanding the Caspase-11 pathway's interaction with microbiota and immune cells is crucial for PD pathogenesis.

Purpose of the Study:

• To investigate the role of Caspase-11-mediated noncanonical pyroptosis in periodontitis.
• To explore the interplay between Caspase-11, subgingival microbiota, and macrophage polarization in PD.
• To elucidate the mechanism linking Caspase-11 to alveolar bone resorption in PD.

Main Methods:

• Analysis of clinical samples from PD patients for Caspase-4 and gasdermin-D expression.
• Single-cell sequencing to identify Caspase-4-expressing cells in gingival tissues.
• In vitro macrophage experiments with *P.g* and Caspase-11 deficient cells.
• Experimental PD mouse models using Caspase-11 deficient and wild-type mice, including cohousing studies.

Main Results:

• PD patients exhibited increased Caspase-4 and gasdermin-D activation, indicating noncanonical pyroptosis.
• Caspase-4 was predominantly found in gingival macrophages.
• Caspase-11 deficiency in mice reduced *P.g*-induced pyroptosis, altered subgingival microbiota, decreased M1 macrophage polarization, and attenuated alveolar bone resorption.

Conclusions:

• Caspase-11 plays a critical role in noncanonical pyroptosis during periodontitis pathogenesis.
• Caspase-11 influences subgingival microbiota composition and promotes M1 macrophage polarization, contributing to alveolar bone loss.
• Targeting Caspase-11-mediated pyroptosis presents a potential therapeutic strategy for periodontitis.