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Published on: January 7, 2019
BPTES inhibits anthrax lethal toxin-induced inflammatory response
Jinling Wang1, Daowei Yang1, Xizi Shen2
1Department of Emergency, Zhongshan Hospital of Xiamen University, Xiamen 361005, China.
Abstract:
Bacillus anthracis is a lethal agent of anthrax disease and the toxins are required in anthrax pathogenesis. The anthrax lethal toxin can trigger NLRP1b inflammasome activation and pyroptosis. Although the underlying mechanism is well understood, the medications targeting the NLRP1b inflammasome are not available in the clinic. Herein, we describe that BPTES, a known Glutaminase (GLS) inhibitor, is an effective NLRP1b inflammasome inhibitor. BPTES could effectively and specifically suppress NLRP1b inflammasome activation in macrophages but have no effects on NLRP3, NLRC4 and AIM2 inflammasome activation. Mechanistically, BPTES alleviated the UBR2 mediated proteasomal degradation pathway of the NLRP1b N terminus, thus blocking the release of the CARD domain for subsequent caspase-1 processing. Furthermore, BPTES could prevent disease progression in mice challenged with the anthrax lethal toxin. Taken together, our studies indicate that BPTES can be a promising pharmacological inhibitor to treat anthrax lethal toxin-related inflammatory diseases.
Insights
Bacillus anthracis lethal toxin triggers NLRP1b inflammasome activation. A Glutaminase inhibitor, BPTES, effectively blocks this activation and prevents anthrax toxin-induced disease progression in mice.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Bacillus anthracis lethal toxin is a key factor in anthrax pathogenesis, inducing NLRP1b inflammasome activation and pyroptosis.
- Current therapeutic options targeting NLRP1b inflammasome are lacking for clinical use.
Purpose of the Study:
- To identify and characterize novel inhibitors of NLRP1b inflammasome activation.
- To evaluate the therapeutic potential of BPTES, a Glutaminase inhibitor, against anthrax lethal toxin-induced inflammation.
Main Methods:
- Assessed BPTES's effect on NLRP1b inflammasome activation in macrophages.
- Investigated the specificity of BPTES against other inflammasomes (NLRP3, NLRC4, AIM2).
- Elucidated the molecular mechanism of BPTES action, focusing on proteasomal degradation pathways.
- Evaluated BPTES efficacy in a murine model of anthrax lethal toxin challenge.
Main Results:
- BPTES specifically inhibited NLRP1b inflammasome activation in macrophages without affecting NLRP3, NLRC4, or AIM2.
- BPTES was found to prevent the UBR2-mediated proteasomal degradation of the NLRP1b N terminus.
- This inhibition blocked caspase-1 processing and subsequent pyroptosis.
- BPTES treatment significantly ameliorated disease progression in mice challenged with anthrax lethal toxin.
Conclusions:
- BPTES is a potent and specific inhibitor of NLRP1b inflammasome activation.
- BPTES demonstrates therapeutic potential for treating inflammatory diseases caused by Bacillus anthracis lethal toxin.
- BPTES represents a promising pharmacological candidate for future clinical development against anthrax toxin-related conditions.
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