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Innate Immun. 2014 Apr;20(3):290-300. doi: 10.1177/1753425913490575. Epub 2013 Jun 21.

Alarmin HNP-1 promotes pyroptosis and IL-1β release through different roles of NLRP3 inflammasome via P2X7 in LPS-primed macrophages.

Author information

1
1Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

Abstract

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 α-defensin subfamily, could regulate the IL-1β 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-1β 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-1β release. Incubation of LPS-primed macrophages with potassium chloride also prevented HNP-1-induced export of mature IL-1β. 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-1β 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.

KEYWORDS:

Defensin; cytokine; immunomodulation; pyroptosis; signal transduction

PMID:
23792296
DOI:
10.1177/1753425913490575
[Indexed for MEDLINE]

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