Abstract
The nucleotide-binding domain and leucine-rich repeat-containing receptor with a pyrin domain 3 (NLRP3) inflammasome is a sensor for different types of infections and alterations of homeostatic parameters, including abnormally high levels of the extracellular nucleotide ATP or crystallization of different metabolites. All NLRP3 activators trigger a similar intracellular pathway, where a decrease in intracellular K+ concentration and permeabilization of plasma membrane are key steps. Cationic amphipathic antimicrobial peptides and peptide toxins permeabilize the plasma membrane. In fact, some of them have been described to activate the NLRP3 inflammasome. Among them, the bee venom antimicrobial toxin peptide melittin is known to elicit an inflammatory reaction via the NLRP3 inflammasome in response to bee venom. Our study found that melittin induces canonical NLRP3 inflammasome activation by plasma membrane permeabilization and a reduction in the intracellular K+ concentration. Following melittin treatment, the apoptosis-associated speck-like protein, an adaptor protein with a caspase recruitment domain (ASC), was necessary to activate caspase-1 and induce IL-1β release. However, cell death induced by melittin prevented the formation of large ASC aggregates, amplification of caspase-1 activation, IL-18 release and execution of pyroptosis. Therefore, melittin-induced activation of the NLRP3 inflammasome results in an attenuated inflammasome response that does not result in caspase-1 dependent cell death.
Highlights
We have described that the cytotoxic antimicrobial peptide known as melittin produces plasma membrane disruption with a concomitant decrease in intracellular K+ concentration, driving the canonical NLR with a pyrin domain 3 (NLRP3) inflammasome activation
Melittin-induced plasma membrane permeabilization leads to rapid cytotoxicity that impairs the formation of large a caspase recruitment domain (ASC) aggregates and the execution of pyroptosis, denoting that necrotic cell death induced by this antimicrobial peptide toxin, similar to other plasma membrane disrupting agents, could preclude pyroptosis
We examined the function of four cationic natural amphipathic antimicrobial peptides in the activation of the NLRP3 inflammasome: (a) LL-37, the only human cathelicidin peptide produced by a variety of cells, including monocytes; (b) temporin A, an antimicrobial peptide produced by the skin of the European frog Rana temporaria; (c) Indolicidin, a peptide present in the cytoplasmic granules of bovine neutrophils; and (d) melittin, a peptide toxin produced by bees and with high microbicidal activity.[17,23,31]
Summary
Inflammasomes are multiprotein complexes activated in response to multiple pathogen and noninfectious stimuli, including pore-forming toxins, venoms, changes in extracellular osmolarity or extracellular accumulation of metabolites such as ATP or crystalline uric acid.[1,2,3,4,5] Inflammasomes are formed by a sensor protein that usually belongs to the nucleotide-binding domain and leucine-rich repeat-containing receptor (NLR) family, among them, the sensor NLR with a pyrin domain 3 (NLRP3), the inflammasome most thoroughly investigated and the only one able to respond to sterile stimulation.[1,2] The canonical NLRP3 inflammasome is formed by the sensor protein NLRP3, the adaptor protein apoptosisassociated speck-like protein with a caspase recruitment domain (ASC) and the effector protease caspase-1.1,2,6. Antimicrobial peptides form a chemical barrier against invading pathogens. These peptides must be massively inserted into the targeted membrane to attain their lethal mechanism, a process facilitated by their amphipathic nature. The final step is severe membrane distortion or pore formation in the target cell, with lethal leakage of intracellular metabolites and ions.[17]
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