Distinct Licensing of IL-18 and IL-1β Secretion in Response to NLRP3 Inflammasome Activation

Rebecca L Schmidt,Laurel L Lenz,David M Ojcius

doi:10.1371/journal.pone.0045186

Rebecca L Schmidt, Laurel L Lenz + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0045186

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Journal: PloS one	Publication Date: Sep 18, 2012
Citations: 82	License type: CC BY 4.0

Affiliation: National Jewish Health, University of Colorado Denver

Abstract

Inflammasome activation permits processing of interleukins (IL)-1β and 18 and elicits cell death (pyroptosis). Whether these responses are independently licensed or are “hard-wired” consequences of caspase-1 (casp1) activity has not been clear. Here, we show that that each of these responses is independently regulated following activation of NLRP3 inflammasomes by a “non-canonical” stimulus, the secreted Listeria monocytogenes (Lm) p60 protein. Primed murine dendritic cells (DCs) responded to p60 stimulation with reactive oxygen species (ROS) production and secretion of IL-1β and IL-18 but not pyroptosis. Inhibitors of ROS production inhibited secretion of IL-1β, but did not impair IL-18 secretion. Furthermore, DCs from caspase-11 (casp11)-deficient 129S6 mice failed to secrete IL-1β in response to p60 but were fully responsive for IL-18 secretion. These findings reveal that there are distinct licensing requirements for processing of IL-18 versus IL-1β by NLRP3 inflammasomes.

Highlights

Inflammasomes regulate the processing of pro-IL-1b and proIL-18 by caspase-1 [1], as well as inflammatory cell death [2]
Infection of bone marrow-derived DCs (BMDCs) by Listeria monocytogenes (Lm) induced secretion of IL-18 and IL1b, which was significantly reduced upon infection with Dp60 Lm (Fig. 1A,B)
To distinguish whether p60 acted directly on dendritic cells (DCs) or indirectly by altering the bacterial cell, we evaluated IL-1b and IL-18 secretion by BMDCs treated with detoxified recombinant p60 protein [27]

Summary

Introduction

Inflammasomes regulate the processing of pro-IL-1b and proIL-18 by caspase-1 (casp1) [1], as well as inflammatory cell death (pyroptosis) [2]. In the case of NLRP3 inflammasomes, these factors include microbial proteins, crystalline urea, RNA, Alum, and ATP [3,4,5,6,7,8] The diversity of these activating stimuli implies that complex regulatory mechanisms govern NLRP3-dependent responses. Recent findings further suggest that casp or casp can impact the response of NLRP3 inflammasomes to certain pathogen-derived ‘‘non-canonical’’ stimuli [10,11]. It is not known whether ROS participate in responses to such stimuli. It remains unclear whether processing of IL-18 requires ROS production or might instead be regulated by distinct ROS-independent licensing mechanisms

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