Tryptanthrin suppresses multiple inflammasome activation to regulate NASH progression by targeting ASC protein

Area of Science:

• Immunology
• Pharmacology
• Molecular Biology

Background:

• The adaptor protein ASC is crucial for inflammasome activation via PYD and CARD interactions.
• Despite ASC's central role, targeted therapies remain limited.
• Tryptanthrin (TPR) was identified as a potential inhibitor of NLRP3 inflammasome activation.

Purpose of the Study:

• To investigate TPR's impact on NLRP3, NLRC4, and AIM2 inflammasomes.
• To elucidate the underlying anti-inflammatory mechanisms of TPR.
• To evaluate TPR's efficacy in methionine- and choline-deficient (MCD)-induced NASH and LPS-induced sepsis mouse models.

Main Methods:

• In vitro studies utilized bone marrow-derived macrophages for assessing anti-inflammatory activity.
• Techniques included western blot, ion flux assays, immunofluorescence, ELISA, co-immunoprecipitation, ASC oligomerization assays, SPR, and molecular docking.
• In vivo efficacy was evaluated in LPS-induced sepsis and MCD-induced NASH mouse models.

Main Results:

• TPR demonstrated inhibition of NLRP3, NLRC4, and AIM2 inflammasome activation.
• TPR treatment significantly alleviated disease progression in mouse models of NASH and sepsis.
• TPR was found to interrupt ASC interactions with NLRP3/NLRC4/AIM2 and bind to the PYD domain of ASC.

Conclusions:

• TPR acts as a novel broad-spectrum inflammasome inhibitor by targeting ASC.
• Its ability to inhibit multiple inflammasomes suggests potential therapeutic applications for diverse inflammatory conditions.