Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida

Area of Science:

• Immunology
• Cellular Biology
• Infectious Disease

Background:

• The Absent in Melanoma 2 (AIM2) inflammasome detects microbial DNA, initiating immune responses.
• Pyroptosis, a form of inflammatory cell death, is triggered by inflammasomes but its precise role in AIM2-mediated immunity is unclear.
• Gasdermin D (GSDMD) is the known executor of pyroptosis via membrane pore formation.

Purpose of the Study:

• To investigate the role of Gasdermin D (GSDMD) in the host immune response to Francisella tularensis subspecies novicida (F. novicida) infection.
• To determine the function of pyroptosis downstream of the AIM2 inflammasome.
• To elucidate the relationship between GSDMD, caspase-1 activation, and AIM2 inflammasome signaling.

Main Methods:

• Utilized GSDMD-deficient mice and wild-type controls for infection studies.
• Analyzed bone marrow-derived macrophages (BMDMs) from GSDMD-deficient and wild-type mice.
• Stimulated BMDMs with F. novicida, poly(dA:dT), and mouse cytomegalovirus (MCMV) to assess inflammasome activation.

Main Results:

• GSDMD-deficient mice exhibited increased susceptibility to F. novicida infection.
• GSDMD was essential for optimal caspase-1 activation and pyroptosis in F. novicida-infected BMDMs.
• Caspase-1 activation was impaired in GSDMD-deficient BMDMs stimulated with various AIM2 inflammasome activators.

Conclusions:

• Gasdermin D (GSDMD) plays a critical role in host defense against F. novicida.
• GSDMD is required for efficient caspase-1 activation and pyroptosis downstream of the AIM2 inflammasome.
• This study reveals a novel function for GSDMD in potentiating AIM2 inflammasome-mediated caspase-1 activation.