Dicer regulates activation of the NLRP3 inflammasome.

David M Ojcius,Christian W Schindler,Ardavan Jafari,Ali A Abdul-Sater,Laxmi Yeruva

doi:10.1371/journal.pone.0215689

Abstract

Inflammation plays a critical role in initiation of adaptive immunity, pathogen clearance and tissue repair. Interleukin (IL)-1β is a potent pro-inflammatory cytokine and therefore its production is tightly regulated: its secretion requires the assembly of a macromolecular protein complex, termed the inflammasome. Aberrant activation of the inflammasome has been linked to debilitating human diseases including chronic inflammatory and autoimmune diseases. Thus, there is a great interest in understanding how inflammasomes are regulated. Here we show that Dicer, an enzyme necessary for the production of mature micro-RNAs (miRNAs), is required for optimal activation of NLRP3 inflammasomes in bone marrow macrophages. Our data indicate that miRNAs may play an important role in promoting inflammasome activation.

Highlights

The innate immune system employs germ line encoded pattern recognition receptors (PRRs) that recognize “molecular patterns” from microbes, environmental stressors and damaged tissue
Dicer regulates activation of the NLRP3 inflammasome with S+ media (RPMI 1640 supplemented with 10% Fetal Bovine Serum, non-essential amino acids, 2-mercaptoethanol, sodium pyruvate and penicillin-streptomycin), and RBCs were lysed with RBC lysis buffer before being plated into 100 mm Petri dishes containing S+ media containing 20% L929-conditioned media to drive their differentiation into macrophages
Given the significance of inflammasome regulation in controlling inflammation and associated human diseases, we explored whether microRNAs under the control of Dicer play a role in NLRP3 inflammasome activation

Summary

Introduction

The innate immune system employs germ line encoded pattern recognition receptors (PRRs) that recognize “molecular patterns” from microbes, environmental stressors and damaged tissue. Once activated, these receptors initiate robust inflammatory responses that include the secretion of potent inflammatory cytokines such as Interleukin (IL)-1β, IL-6, TNF-α and Interferons (IFNs) [1,2,3]. The first signal entails transcription of the IL-1β gene, but the gene product, pro-IL1β is not active. The second signal entails activation of the inflammasome, a multimeric protein complex typically composed of an NLR protein, the adapter protein ASC and the inactive zymogen caspase-1. Caspase-1 is activated and directs the cleavage of pro-IL1β into active and secreted IL-1β

Methods

Results

Conclusion