1. Exploring Candesartan, an angiotensin II receptor antagonist, as a novel inhibitor of NLRP3 inflammasome: alleviating inflammation in Neisseria gonorrhoeae infection.
- Author
-
Lin WY, Tsui JL, Chiu HW, Wong WT, Wu CH, Hsu HT, Ho CL, Yeh SP, Rao YK, Chen A, Wang CC, Hsu CH, Chernikov OV, Hua KF, and Li LH
- Subjects
- Animals, Mice, Tetrazoles pharmacology, NF-kappa B metabolism, Reactive Oxygen Species metabolism, Interleukin-1beta metabolism, Interleukin-1beta genetics, Angiotensin Receptor Antagonists pharmacology, Angiotensin Receptor Antagonists therapeutic use, Humans, RAW 264.7 Cells, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Inflammasomes metabolism, Inflammasomes immunology, Inflammasomes drug effects, Neisseria gonorrhoeae drug effects, Neisseria gonorrhoeae immunology, Benzimidazoles pharmacology, Benzimidazoles therapeutic use, Gonorrhea drug therapy, Gonorrhea microbiology, Gonorrhea immunology, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Inflammation drug therapy, Biphenyl Compounds pharmacology
- Abstract
Background: Gonorrhea, induced by Neisseria gonorrhoeae infection, stands as a prevalent sexually transmitted inflammatory disease globally. Our earlier research illuminated that N. gonorrhoeae-infected macrophages provoke inflammation by activating the intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, a pivotal regulator in inflammatory diseases governing the maturation and secretion of interleukin (IL)-1β and IL-18. Nevertheless, effective therapies addressing N. gonorrhoeae-mediated NLRP3 inflammasome activation and ensuing inflammation are currently lacking. This study delves into the impact of the angiotensin II receptor antagonist Candesartan (CS) on N. gonorrhoeae-infected macrophages., Methods: The protein expression levels were examined through ELISA and Western blotting. Intracellular H
2 O2 levels, mitochondrial reactive oxygen species, and mitochondrial membrane integrity were evaluated using targeted fluorescent probes and analyzed via flow cytometry. NF-κB transcriptional activity was assessed using NF-κB reporter cells. LC3-knockdown cells were created using CRISPR/Cas9 technology., Results: CS effectively inhibits the NLRP3 inflammasome, as indicated by the suppression of caspase-1 activation, IL-1β secretion, NLRP3 release, and the release of apoptosis-associated speck-like protein containing a CARD (ASC) in N. gonorrhoeae-infected J774A.1 macrophages. Additionally, CS selectively impedes IL-6 secretion and iNOS expression in both N. gonorrhoeae-infected J774A.1 and RAW264.7 macrophages. Mechanistic insights uncover the inhibition of NF-κB by CS in N. gonorrhoeae-infected J774A.1 macrophages, while intracellular H2 O2 generation, mitogen-activated protein kinases phosphorylation, and mitochondrial damage remain unaffected. Notably, our study highlights that CS-induced autophagy contributes partially to its inhibitory effect on the NLRP3 inflammasome., Conclusions: These results underscore the potential of CS as an anti-inflammatory drug for the treatment of gonorrhea, addressing a critical unmet medical need in combating N. gonorrhoeae-induced inflammation., Competing Interests: Declarations. Ethics approval and consent to participate: The acquisition of whole blood strictly followed the guidelines and regulations set forth and sanctioned by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center, as detailed in references TSGH-IRB-2-106-05-190 and TSGH-IRB-2-106-05-009. Prior to the initiation of the study, informed consent was obtained from all participating individuals, and the documentation thereof was securely maintained within the Department of Laboratory Medicine at the Linsen, Chinese Medicine, and Kunming Branch of the Taipei City Hospital in Taipei, Taiwan. The bacterial infection experiments were conducted with the approval of the Taiwan CDC, under the designated approval number 098013. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF