Cutting Edge: Cyclic Polypeptide and Aminoglycoside Antibiotics Trigger IL-1β Secretion by Activating the NLRP3 Inflammasome

Abstract

Clinical use of antibiotics is based on their capacity to inhibit bacterial growth via bacteriostatic or bacteriocidal effects. In this article, we show that the aminoglycoside antibiotic neomycin, the cyclic lipopeptide antibiotic polymyxin B, and the cyclic peptide antibiotics gramicidin and tyrothricin can induce IL-1β secretion in bone marrow dendritic cells and macrophages. LPS priming was required to trigger the transcription and translation of pro–IL-1β but was independent of TNFR or IL-1R signaling. All four antibiotics required the NLRP3 inflammasome, the adaptor ASC, and caspase-1 activation to secrete IL-1β, a process that depended on potassium efflux but was independent of P2X7 receptor. All four antibiotics induced neutrophil influx into the peritoneal cavity of mice, which required NLRP3 only in the case of polymyxin B. Together, certain antibiotics have the potential to directly activate innate immunity of the host.

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion

“…Our in vitro studies confirmed that phagocytic uptake was required for CaOx-induced IL-1β secretion in DCs, an observation consistent with the mode of NLRP3 activation by monosodium urate and calcium pyrophosphate crystals (12), silica (14), asbestos (14), and cholesterol crystals (13) in other disease contexts. Potassium efflux from the cell, occurring upon cell membrane disruption or pore formation by bacterial toxins, is another trigger of NLRP3 activation in DCs (15,29). CaOx crystal-induced NLRP3 activation also depended on this mechanism, which was again consistent with previous reports on crystals of asbestos, monosodium urate (14), silica (30), cholesterol (31), and calcium phosphate (32).…”

Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4

“…BMDCs were generated by established protocols as described elsewhere. 46 Necrotic cell supernatants were prepared from mouse tubular cells by repeated freezing and thawing or hydrogen peroxide (H 2 O 2 ; 1mM) treatment for 24 hours. RPMI 1640 GlutaMAX-I medium (Invitrogen, Carlsbad, CA) was supplemented with 10% (vol/vol) FBS (Biochrom AG, Berlin, Germany), 1% of penicillin and streptomycin (PAA Laboratories GmbH, Pasching, Austria).…”

“…46 Anti-IkB-a, anti-phospho p38, antitotal p38, and anti-histone H4 antibodies were from Cell Signaling Technology (Danvers, MA).…”

G Protein Signaling Modulator-3 Inhibits the Inflammasome Activity of NLRP3

“…Inflammasome-dependent IL-1␤ production requires initial priming using lipopolysaccharide (LPS) to induce pro-IL-␤ synthesis (31,32). Following LPS stimulation, different inflammasome activators were added, and mature IL-1␤ secreted in the medium was quantified.…”