Journal
INNATE IMMUNITY
Volume 20, Issue 3, Pages 290-300Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1753425913490575
Keywords
immunomodulation; cytokine; pyroptosis; signal transduction; Defensin
Categories
Funding
- National Science Fund for Distinguished Young Scholars [30825037]
- National Natural Science Foundation of China [81130036]
- Changjiang Scholar Program of China
- Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents
Ask authors/readers for more resources
Defensins are the first endogenous mediators to be characterized as alarmins and play multifunctional roles in immune response. Previous studies reported that human neutrophil peptide (HNP)-1, a member of the alpha-defensin subfamily, could regulate the IL-1 beta post-translational process; however, the underlying mechanism remained unknown. Using an LPS-primed THP-1 macrophage model, we found that inhibition of P2X purinoceptor 7 (P2X7) suppressed HNP-1-initiated mature IL-1 beta release. Confocal microscopy and glutathione S-transferase (GST) pull-down assay demonstrated that HNP-1 bound to P2X7 directly. HNP-1 treatment increased the activated level of caspase-1, and inhibition of caspase-1 abolished IL-1 beta release. Incubation of LPS-primed macrophages with potassium chloride also prevented HNP-1-induced export of mature IL-1 beta. Likewise, an ethidium bromide uptake test showed that the P2X7-K+ efflux-caspase-1 signaling pathway triggered by HNP-1 contributed to pyroptotic pore formation. Furthermore, knock down of inflammasome adaptor Nod-like receptor family pyrin domain containing 3 (NLRP3) decreased activated caspase-1 level and reduced pore formation in macrophages, whereas IL-1 beta release was not significantly impaired. These findings not only illustrated the mechanism for alarmin HNP-1 in enhancing inflammatory response, but also provided therapeutic targets for certain inflammatory diseases in which defensins play important roles.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available