Chicken cathelicidin-2 (CATH-2) as a host defense peptide has been identified to have potent antimicrobial and immunomodulatory activities. Here, we reported the mechanism by which CATH-2 modulates NLRP3 inflammasome activation. Our results show that CATH-2 and ATP as a positive control induced secretion of IL-1β and IL-1α in LPS-primed macrophages but did not affect secretion of IL-6, IL-12 and TNF-α. Furthermore, CATH-2 induced caspase-1 activation and oligomerization of apoptosis-associated speck-like protein containing a carboxy- terminal caspase recruitment domain (ASC), which is essential for NLRP3 inflammasome activation. However, CATH-2 failed to induce IL-1β secretion in Nlrp3, Asc and Casp1 macrophages. Notably, IL-1β and NLRP3 mRNA expression were not affected by CATH-2. In addition, CATH-2-induced NLRP3 inflammasome activation was mediated by K efflux but independent of the P2X7 receptor that is required for ATP-mediated K efflux. Gene interference of NEK7 kinase which has been identified to directly interact with NLRP3, significantly reduced IL-1β secretion and caspase-1 activation induced by CATH-2. Furthermore, confocal microscopy shows that CATH-2 significantly induced lysosomal leakage with the diffusion of dextran fluorescent signal. Cathepsin B inhibitors completely abrogated IL-1β secretion and caspase-1 activation as well as attenuating the formation of ASC specks induced by CATH-2. These results all indicate that CATH-2-induced activation of NLRP3 inflammasome is mediated by K efflux, and involves the NEK7 protein and cathepsin B. In conclusion, our study shows that CATH-2 acts as a second signal to activate NLRP3 inflammasome. Our study provides new insight into CATH-2 modulating immune response.
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http://dx.doi.org/10.1186/s13567-022-01083-4 | DOI Listing |
J Agric Food Chem
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Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
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Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
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View Article and Find Full Text PDFJ Cardiovasc Transl Res
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Department of Cardiology, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, 215000, China.
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View Article and Find Full Text PDFSci Rep
January 2025
Department of Basic Sciences, Faculty of Dentistry, Universidad de Antioquia U de A, Medellín, 050010, Colombia.
The NLRP3 inflammasome, regulated by TLR4, plays a pivotal role in periodontitis by mediating inflammatory cytokine release and bone loss induced by Porphyromonas gingivalis. Periodontal disease creates a hypoxic environment, favoring anaerobic bacteria survival and exacerbating inflammation. The NLRP3 inflammasome triggers pyroptosis, a programmed cell death that amplifies inflammation and tissue damage.
View Article and Find Full Text PDFInt Immunopharmacol
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The complement system plays a crucial role in various pathophysiological conditions, including snake envenomation. In this study, we investigated the effects of Bitis arietans venom on the complement system using an ex vivo human whole blood model. Our findings demonstrate that B.
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