Cholesterol-dependent cytolysins induce rapid release of mature IL-1β from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner

Abstract

CDC are exotoxins secreted by many Gram-positive bacteria that bind cholesterol and oligomerize to form pores in eukaryotic cell membranes. We demonstrate that CDC TLO induces caspase-1 cleavage and the rapid release of IL-1beta from LPS-primed murine BMDM. IL-1beta secretion depends on functional toxin pore formation, as free cholesterol, which prevents TLO binding to cell membranes, blocks the cytokine release. Secretion of the mature forms of IL-1beta and caspase-1 occurs only at lower TLO doses, whereas at a higher concentration, cells release the biologically inactive proforms. IL-1beta release at a low TLO dose requires potassium efflux, calcium influx, and the activities of calcium-independent PLA(2), caspase-1, and cathepsin B. Additionally, mature IL-1beta release induced by a low TLO dose is dependent on the NLRP3 inflammasome, and pro-IL-1beta release induced by a high TLO dose occurs independently of NLRP3. These results further elucidate a mechanism of CDC-induced IL-1beta release and suggest a novel, immune evasion strategy in which IL-1beta-containing macrophages might release primarily inactive cytokine following exposure to high doses of these toxins.

Listeriolysin O-Dependent Bacterial Entry into the Cytoplasm Is Required for Calpain Activation and Interleukin-1α Secretion in Macrophages Infected withListeria monocytogenes

“…Further studies are currently under way to elucidate the exact mechanisms involved. It will be intriguing to determine in the further study whether such a late-stage increase in intracellular calcium levels plays a role in other calcium-dependent cellular processes, which are reported to occur with cholesterol-dependent cytolysins/pore-forming toxins (8,52).…”

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

“…There are many different types of inflammasomes, which are distinguished by their nucleotide-binding oligomerization domain-like receptor (NLRs), adaptors, and stimuli specificity. The NLR family pyrin domain-containing 3 (Nlrp3) inflammasome is activated by endogenous and exogenous stimuli, including the accumulation of uric acid crystals and silica, pore-forming bacterial toxins, b-amyloid, low potassium concentrations, and intracellular reactive oxygen species (13)(14)(15)(16)(17).…”

Apoptosis-Associated Speck–like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1β Response and Host Resistance to Trypanosoma cruzi Infection

“…The different types of inflammasomes are distinguished by their NLRs, adaptors, and stimuli specificities. The NLR pyrin domain-containing 3 (NLRP3) inflammasome, which is possibly the most extensively studied platform, is activated by different stimuli including prokaryotic RNA and different agents that trigger damage-associated molecular patterns (DAMPs), such as urate crystals, pore-forming toxins, and silica, among others (11)(12)(13)(14)(15). It has also been demonstrated that the engagement of the NLRP3 inflammasome requires the generation of reactive oxygen species (ROS), potassium efflux, and lysosomal damage.…”