Distinct changes in endosomal composition promote NLRP3 inflammasome activation.

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Inflammasome complexes are crucial for innate immune responses.
• The NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activates against diverse cellular stressors.
• The precise sensing mechanism initiating NLRP3 inflammasome assembly is not fully understood.

Purpose of the Study:

• To elucidate the primary sensing mechanism by which NLRP3 inflammasome activators initiate inflammasome assembly.
• To identify the converging pathway utilized by various NLRP3 inflammasome activators.

Main Methods:

• Investigated the role of endoplasmic reticulum-endosome membrane contact sites (EECS) in inflammasome activation.
• Analyzed the impact of EECS disruption on endosomal phosphatidylinositol 4-phosphate (PI4P) levels and trafficking.
• Examined the recruitment of NLRP3 to endosomes and inflammasome activation.
• Utilized mouse models with defects in endosome-to-trans-Golgi network trafficking (ETT) in myeloid cells.

Main Results:

• NLRP3 inflammasome activators converge on disrupting EECS.
• Disruption of EECS leads to PI4P accumulation and impaired endosome-to-trans-Golgi network trafficking (ETT).
• Impaired ETT and PI4P accumulation are necessary for NLRP3 recruitment to endosomes and inflammasome activation.
• Defects in myeloid ETT increase susceptibility to lipopolysaccharide-induced sepsis in mice.

Conclusions:

• NLRP3 inflammasome activation is initiated by the disruption of EECS.
• Endosomal PI4P accumulation and impaired ETT are critical steps for NLRP3 inflammasome assembly.
• This study identifies a novel cellular mechanism regulating NLRP3 inflammasome activation and innate immunity.