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Review
. 2019 May 1:10:451.
doi: 10.3389/fphar.2019.00451. eCollection 2019.

MicroRNA Post-transcriptional Regulation of the NLRP3 Inflammasome in Immunopathologies

Gulcin Tezcan  1 , Ekaterina V Martynova  1 , Zarema E Gilazieva  1 , Alan McIntyre  2 , Albert A Rizvanov  1 , Svetlana F Khaiboullina  1   3
Affiliations
Review

MicroRNA Post-transcriptional Regulation of the NLRP3 Inflammasome in Immunopathologies

Gulcin Tezcan et al. Front Pharmacol. .

Abstract

Inflammation has a crucial role in protection against various pathogens. The inflammasome is an intracellular multiprotein signaling complex that is linked to pathogen sensing and initiation of the inflammatory response in physiological and pathological conditions. The most characterized inflammasome is the NLRP3 inflammasome, which is a known sensor of cell stress and is tightly regulated in resting cells. However, altered regulation of the NLRP3 inflammasome is found in several pathological conditions, including autoimmune disease and cancer. NLRP3 expression was shown to be post-transcriptionally regulated and multiple miRNA have been implicated in post-transcriptional regulation of the inflammasome. Therefore, in recent years, miRNA based post-transcriptional control of NLRP3 has become a focus of much research, especially as a potential therapeutic approach. In this review, we provide a summary of the recent investigations on the role of miRNA in the post-transcriptional control of the NLRP3 inflammasome, a key regulator of pro-inflammatory IL-1β and IL-18 cytokine production. Current approaches to targeting the inflammasome product were shown to be an effective treatment for diseases linked to NLRP3 overexpression. Although utilizing NLRP3 targeting miRNAs was shown to be a successful therapeutic approach in several animal models, their therapeutic application in patients remains to be determined.

Keywords: NLRP3; disease; inflammasome; inflammation; microRNA.

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Figures

FIGURE 1
FIGURE 1
NLRP3 inflammasome activation. There are two signals required for NLRP3 inflammasome activation. Signal 1 is a priming trigger (microbial ligands, cytokines, etc.) required for the upregulation of NLRP3 and pro-IL-1β transcription and protein synthesis. Signal 2 is an activation trigger (ATP, toxins, viral RNA, etc.) which is essential for formation of an active NLRP3 inflammasome. The second stimulus promotes NLRP3, PC1, pro-IL-1β, and pro-IL-18 protein synthesis. The N-terminal NBD of NLRP3 polymerizes initiating PYD–PYD oligomerization with ASC. The CARD of ASC recruits PC1, which become cleaved liberating AC1. Inflammatory AC1 liberates functional IL-1β and IL-18, pleotropic cytokines regulating inflammation and innate immune response.
FIGURE 2
FIGURE 2
miRNA regulation of NLRP3 inflammasome expression. (A) Priming signal triggers NLRP3, PC1, IL-1β, and IL-18 transcription and protein synthesis. Activation signal initiates inflammasome formation and release of AC1. AC1 proteolytically cleaves pro-IL-1β and pro-IL-18, liberating active cytokines. (B) Suppression of NLRP3 protein translation and inflammasome formation by miRNA. Priming stimulus triggers NLRP3 transcription; however, miR-223, miR-22, miR-30e, and miR-7 bind to the UTR region of NLRP3 mRNA and interrupt protein translation. Absence of NLRP3 protein leads failure of the inflammasome protein complex formation, when the second stimulus present.
FIGURE 3
FIGURE 3
UTR binding sites of NLRP3 for miRNAs responsible for the regulation of inflammation.
See this image and copyright information in PMC

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