MicroRNAs as important regulators of the NLRP3 inflammasome

Progress in Biophysics and Molecular Biology xxx (xxxx) xxx

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Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio

MicroRNAs as important regulators of the NLRP3 inflammasome Parvin Zamani a, Reza Kazemi Oskuee b, Stephen L. Atkin c, Jamshid Gholizadeh Navashenaq d, Amirhossein Sahebkar e, f, g, * a

Nanotechnology Research Center, Student Research Committee, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran b Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran c Weill Cornell Medicine Qatar, Doha, Qatar d Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran e Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran f Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran g School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 December 2018 Accepted 13 May 2019 Available online xxx

Inflammasomes are a group of cytosolic multi-protein signaling complexes that regulate maturation of the interleukin (IL)-1 family cytokines IL-1b and IL-18 through activation of inflammatory caspase-1. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is the best characterized and consists of several key components that are assembled and activated in response to different endogenous and exogenous signals. The NLRP3 inflammasome is common to a number of human inflammatory diseases and its targeting may lead to novel anti-inflammatory therapy. NLRP3 inflammasome activation is tightly regulated by different mechanisms especially post-transcriptional modulation via microRNAs (miRNA). MicroRNAs are small endogenous noncoding RNAs that are 21e23 nucleotides in length and control the expression of various genes through binding to the 30 -untranslated regions of the respective mRNA and subsequent post-transcriptional regulation. MicroRNAs have recently been recognized as crucial regulators of the NLRP3 inflammasome. In this review, we summarize the current understanding of the role of miRNAs in the regulation of NLRP3 inflammasome complexes and their impact on the pathogenesis of inflammatory disease processes. © 2019 Elsevier Ltd. All rights reserved.

Keywords: MicroRNA NLRP3 inflammasomes Caspase-1 IL-18 IL-1b Inflammation

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NLRP3 inflammasomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Activation of the NLRP3 inflammasome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NLRP3 activation models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NLRP3 inflammasome in disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NLRP3 and miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-223 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-20a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-23a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-30e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-33 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-132 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, P.O. Box: 91779-48564, Iran. E-mail addresses: [email protected], [email protected] (A. Sahebkar). https://doi.org/10.1016/j.pbiomolbio.2019.05.004 0079-6107/© 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004

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16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

miR-133 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-146 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-155 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-296 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-377 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-148 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-302 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-193 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miR-711 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Inflammation is an innate protective response that is initiated by different internal and external harmful stimuli, such as foreign pathogens, dead cells or variety of environmental irritants, and strongly regulated by the host. Inflammation is important in tissue repair and protection from persistent infection by pathogens, though an inadequate inflammatory response my result in chronic ~ ez, 2010). The or systemic inflammatory diseases (Chen and Nun innate immune response depends upon recognition of patternrecognition receptors (PRRs) to targeted pathogen-associated molecular patterns (PAMPs), derived from pathogenic microbes and danger-associated molecular patterns (DAMPs). PRRs are expressed mainly in immune and inflammatory cells such as monocytes, neutrophils, antigen-presenting cell (APC) including macrophages and dendritic cells (Fullard and O'Reilly, 2015; Schnaars et al., 2013). Activation of PRRs by PAMPs or DAMPs leads to the induction of the inflammatory response that is initiated by the secretion of proinflammatory cytokines and type I interferons (interferon-a and interferon-b) (Guo et al., 2015). Inflammasomes are multiple intracellular protein complexes that when activated play an important role in the innate immune system (Martinon et al., 2002). Numerous families of PRRs are the main components of the inflammasome complex, including, the absent in melanoma 2 (AIM)-like receptors (ALRs), nucleotide-binding domain and leucine-rich repeat-containing receptor (NLRP) subfamily (Takeuchi and Akira, 2010). In response to stimuli such as reactive oxygen species (ROS), cholesterol crystals and environmental irritants, assembly is initiated of the main inflammasome components that serve as molecular signaling platforms to activate caspase-1. Active caspase-1 subsequently regulates maturation and cleavage of a pro-infammatory cytokine IL-1 into its bioactive form, IL-1b. In addition, these factors regulate pyroptosis that is a process of proinflammatory programmed cell death that is critical in the pathogenesis of several different diseases (Guo et al., 2015; Lamkanfi and Dixit, 2012), such as alzheimers, atherosclerosis, diabetes, gout and obesity (Garg, 2011; Heneka et al., 2013; Martinon et al., 2006; Masters et al., 2010). Understanding of inflammasome regulation may allow the development of new therapeutic strategies. Several types of inflammasomes have been identified that including NLRP1, NLRP2, NLRP3, AIM2, and IPAF/NLRC4 (Ozaki et al., 2015; Schroder and Tschopp, 2010). The most studied and best characterized inflammasome is NLRP3 that recognizes microbes and endogenous danger signals. The NLRP3 inflammasome is an important mediator of host immune responses and is associated with the development

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of several human chronic inflammatory diseases (Ozaki et al., 2015). The NLRP3 inflammasome complex is regulated by different mechanisms affecting protein and RNA levels, including transcriptional control of gene expression, post-transcriptional modulation via microRNAs (miRNA) and also regulation of NLRP3 inhibitors and activators (Qazi et al., 2013). MicroRNAs (miRNAs) are endogenous single stranded noncoding RNA molecules composed of 21e23 nucleotides in length that are considered as key regulators in RNA silencing. MiRNAs are derived from long RNA hairpins precursor transcripts by the action of nucleases Drosha and Dicer, and play a pivotal role in development and pathological processes in most organisms. They are involved in control of gene expression through post-transcriptional modification or translational repression (Ha and Kim, 2014). Hence, dysregulation of miRNAs are associated with the pathogenesis of several chronic inflammatory diseases such as atherosclerosis, Alzheimer's disease k et al., and multiple sclerosis (Alexander and O'connell, 2015; Nova 2014; Romaine et al., 2015; Smith et al., 2012). To date, several miR classes have been identified that are involved in regulation of the inflammasome (Bandyopadhyay et al., 2013; Qazi et al., 2013; Wang et al., 2017). In this review, we will introduce briefly the molecular mechanisms and regulation of NLRP3 inflammasome activation, followed by evidence on the role of miRNAs involved in the regulation of the inflammasome in different disease conditions. 2. NLRP3 inflammasomes The NLRP3 inflammasome recognizes a wide variety of stimuli including microbial danger signals and also endogenous signals associated with damage such as uric acid crystals, free fatty acids, cholesterol crystals and amyloid-b plaques (Halle et al., 2008; Martinon et al., 2006; Ozaki et al., 2015). NLRP3 is expressed in a number of immune cell types that include monocytes, macrophages, DCs and neutrophils and also epithelial cells, and osteoblasts (Kummer et al., 2007). 3. Activation of the NLRP3 inflammasome Activation of the NLRP3 inflammasome is highly regulated and occurs in two distinct steps including priming (signal 1) and triggering (signal 2) (Ozaki et al., 2015; Sutterwala et al., 2014; Zhong et al., 2013). In the priming step many PAMPs or DAMPs are recognized by toll-like receptors (TLRs) leading to the activation of the nuclear factor kappa B (NF-kB) signaling pathway. This process up-regulates the expression and activation of inflammasome-

Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004

P. Zamani et al. / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx

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related components, including inactive NLRP3, proIL-1b, and proIL18 (Liu et al., 2018; Stutz et al., 2017). The second or triggering step of inflammasome activation is initiated by promoting the oligomerization of NLRP3 that follows the assembly of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1 into a complex, eventually resulting in proteolytic caspase-1-dependent cleavage and the maturation of IL-1b and IL18 in final inflammasome formation (Fig. 1) (Frangogiannis, 2014; Liu et al., 2018).

particulate structures, such as amyloid-b, silica, asbestos and alum are suggested as major triggers of IL-1b secretion by the inflammasome. These irritants are engulfed by phagocytes leading to lysosomal damage that trigger assembly and activation of the NLRP3 inflammasome. In this third model, after lysosomal disruption cathepsin B is released into the cytosol and acts as a direct ligand for NLRP3 activation (Fig. 1) (Schroder and Tschopp, 2010; Shao et al., 2015).

4. NLRP3 activation models

5. NLRP3 inflammasome in disease

Whilst the NLRP3 inflammasome is activated by a wide range of molecules, the exact mechanisms of NLRP3 activation have not been determined, though three models have been proposed for inflammasome activation (Schroder and Tschopp, 2010). The major trigger of the NLRP3 inflammasome in the first model is extracellular ATP that stimulates potassium efflux out of the cell by purogenic P2X7 ATP-gated ion channel activation which consisting of a pannexin-1 hemichannel, resulting in NLRP3 inflammasome activation and assembly (Hari et al., 2014; Schroder and Tschopp, 2010). In the second model, the assembly and activation of the NLRP3 inflammasome is triggered by generation of mitochondrial reactive oxygen species (ROS), such as damage to one or several NADPH oxidative systems by mitochondrial ROS can activate the inflammasome (Schroder and Tschopp, 2010; Shao et al., 2015). In the third model, environmental irritants that form crystalline or

Data suggests that the inappropriate activation of the NLRP3 inflammasome is associated with the initiation and progression of various diseases, such as chronic inflammatory, metabolic diseases, auto-immune and auto-inflammatory diseases and multiple sclerosis (MS) (Goldberg and Dixit, 2015; Jha et al., 2010; Lalor et al., 2011; Ming et al., 2002). In addition, studies suggest that plaque progression in atherosclerotic patients is associated with increase production of IL-1b and IL-18 by the NLRP3 inflammasome (Altaf et al., 2015; Peng et al., 2015). Therefore, activation of the NLRP3 inflammasome needs to be tightly controlled to prevent unwanted host damage, and the initiation and progression of various inflammatory diseases. To date, several regulatory mechanisms have been described in NLRP3 inflammasome activation, but further efforts are needed to identify the exact regulatory mechanisms, NLRP3 complex roles and binding partners.

Fig. 1.

Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004

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6. NLRP3 and miRNAs miRNAs regulate a large number of genes that are involved in the regulation of the NLRP3 inflammasome. In the recent years it has been recognized that microRNAs are essential mediators controlling gene expression through post transcriptional regulation. As shown in Table 1, miRNA plays a pivotal role in the regulation of NLRP3 inflammasomes. Here, we explore the potential roles of miRNA in the regulation of the inflammasome complex specially the NLRP3 complex and associated partners in various inflammatory diseases (Fig. 2). 7. miR-7

a-synuclein is a key mediator in the pathogenesis and progression of Parkinson's disease (PD) that activates microglia and subsequently induces neuroinflammation (Lücking and Brice, 2000). MiR-7 that is expressed and enriched in neurons was able to repress and lower the level of a-synuclein protein in PD (Junn et al., 2009) through miR-7 binding directly to the 30 -UTR of asynuclein mRNA, thus decreasing the level of protein expression through post-transcriptional regulation (Junn et al., 2009). Recent studies showed that aggregated fibrillar a-synuclein is involves in NLRP3 inflammasome activation in monocytes. Fibrillar a-synuclein stimulated microglia cells to synthesis and secrete the proinflammatory cytokine IL-1b through interaction with Toll-like receptor 2 (TLR2), showing that fibrillar a-synuclein released by neuronal degeneration acted as an endogenous trigger for the activation of the NLRP3 inflammasome in PD. In addition, endocytosis of fibrillar a-synuclein resulted in ROS production and release of lysosomal cathepsin B into the cytosol triggering activation of NLRP3 inflammasome and IL-1b production (Codolo et al., 2013). Recent studies have shown that the NLRP3 is a target gene for miR-7, with transfection of miR-7 into microglial cells significantly suppressing NLRP3 inflammasome activation, and anti-miR7 increased inflammasome activation. 8. miR-9 Little research has been done on the role of mir-9 on the inflammasome; however recent studies have reported that ELAV like protein 1 (ELAVL1) plays a key role in induction of inflammatory response that was able to induce caspase-1 and IL-1b leading to pyroptosis (cardiac cell death) in human cardiomyocytes: studies have shown that miR-9 is involved in suppression of the NLRP3 inflammasome in cardiomyocytes through targeting of ELAVL1, subsequently leading to cardiac cell death and heart failure (Jeyabal et al., 2016). It has been recently reported that miR-9 inhibited activation of the NLPR3 inflammasome through targeting of the JAK1/STAT1 signaling pathway with cells treated with JAK1 siRNA plus anti-mir-9 significantly reducing mRNA level and protein expression of IL-1b, caspase-1 and NLRP3 mRNA compared to antimir-9 alone. Therefore, it appears that mir-9 may have a possible anti-inflammatory effect through inhibition of the NLRP3 inflammasome (Wang et al., 2017). 9. miR-223 miR-223 has been shown to be important in the immune system regulation and associated with the development of cancers, inflammatory and autoimmune diseases (Taïbi et al., 2014). Haneklaus et al. reported that miR-223 was involved in the regulation of NLRP3 and IL-11b, showing that miR-223 targeted the NLRP3 30 untranslated region (UTR) and overexpression of miR-223 reduced the expression of NLRP3 protein and suppressed IL-1 ß production

by the inflammasome. In addition, this group identified a virus miRNA (EBV miR-BART15) that was capable of targeting the NLRP3 30 -UTR that prevented activation of the inflammasome with lowering of IL-1b levels (Haneklaus et al., 2012). Others have also reported that the NLRP3 inflammasome is negatively regulated by miR-223 that may differ depending on the myeloid lineage being higher in granulocytes than macrophages and dendritic cells (Bauernfeind et al., 2012). It was also shown that antagonizing miR223 lead to an increase in the expression of NLPR3, which in turn promoted the activity of caspase-1 and enhanced the secretion of IL-1b, though activation of the AIM2-mediated inflammasome remained unaffected. Overexpression of miR-223 attenuated NLRP3 activation in hydrogen peroxide and I/R-induced myocardial damage in vitro and in vivo, suggesting that miR-223 may have a cardioprotective effect in myocardial inflammatory injury by targeting NLRP3 (Meng et al., 2018). These data indicate that miR-223 acts as a posttranscriptional regulator for NLRP3 expression (Bauernfeind et al., 2012). Inflammation contributes to the pathogenesis of chronic hepatitis infection and is associated with NLRP3 activation (Szabo and Petrasek, 2015). miR-223 is also associated with development and progression of hepatocellular carcinoma (HCC) and commonly downregulated in HCC tissues (Wong et al., 2008). Studies have shown that miR-223-3p was capable of significantly suppressing the expression of NLRP3 whilst decreasing cell proliferation and promoting apoptosis in Hep3B cells (Wan et al., 2018). 10. miR-20a NLRP3-inflammasome can be activated by ROS production. TXNIP (thioredoxin-interacting protein), is key player in glucose metabolism and may result in high glucose-induced ROS generation with mitochondrial pathway apoptosis in b-cells (Chen et al., 2008). Under conditions of oxidative stress TXNIP can bind to the NLRP3 inflammasome leading to its activation. Increasing ROS levels result in TXNIP being dissociated from thioredoxin (TRX) and then binds to NLRP3 causing its activation with the formation of active caspase-1 cleavage and production of mature IL-1b from proIL-1b. Hence, TXNIP is considered to be an additional NLRP3 binding partner and is crucial for NLRP3 inflammasome activation (Lu and Holmgren, 2014; Zhou et al., 2010). MiR-20a, belonging to the mir-17-92 cluster, exert as a negative regulator in inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes (RA FLS). mir-20a negatively regulates the expression of the NLRP3 inflammasome by targeting TXNIP in RA FLS, with over-expression of miR-20a leading to decreased activation of the NLRP3 inflammasome that inhibited the secretion of IL-1 and MMP-1. Overexpression of miR-20a reduced the expression of TXNIP, and downregulation of TXNIP by TXNIP-siRNA reduced the expression of the NLRP3-inflammasome, suggesting that TXNIP could be a target for miR-20a (Li et al., 2016). 11. miR-21 miR-21 has been shown to be overexpressed in the lungs of mice treated with bleomycin (BLM) and also in the lungs of patients with idiopathic pulmonary fibrosis (IPF) (Liu et al., 2010). miR-21 acts by targeting sprouty homologue 1 (Spry1) that regulates the ERK-MAP kinase signaling pathway in cardiac fibroblasts (Thum et al., 2008). The NLRP3 inflammasome has been implicated in the development of pulmonary fibrosis (Stout-Delgado et al., 2016; Wree et al., 2014) with the promotion of collagen synthesis and its deposition in the lungs and other tissues (Artlett, 2012). Upregulation of IL-1b through NLRP3 inflammasome stimulation is essential for regulating the host response in the pathogenesis of idiopathic lung

Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004

Type of miRNA

Type of disease

Type of cell

In vivo/in vitro study

Molecular target

Molecular mechanisms

Ref.

miR-7

Parkinson's disease

e

In vitro/In vivo

a-synuclein, NLRP3

(Junn et al., 2009), (Zhou et al., 2016)

miR-9

Atherosclerosis

e

In vitro

ELAVL1, JAK1

miR-223

Myocardial infarction

In vitro/In vivo

NLRP3 30 -UTR

miR-20a

Rheumatoid arthritis

Myeloid cell lineage, Hep3B cells, H9c2 cells RA FLS

In vitro

TXNIP

miR-21

Lung disease

Lung fibroblasts

In vitro

Spry1

miR-23a

Neuropathic pain

HEK293T cells

In vivo/In vitro

CXCR4

miR-30e

Parkinson's disease

e

In vivo

NLRP3

miR-33

Rheumatoid arthritis

Primary peritoneal macrophages

In vitro/patient samples

Not defined

miR-132

e

THP1 cells

In vitro

FOXO3

miR-133a-1

e

THP1 cells

In vitro

UCP2

miR-133b miR-146a

e e

In vivo In vivo

NLRP3 30 -UTR TRAF6/IRAK1

miR-155

Allergic rhinitis Diabetic nephropathy, Gouty arthritis Graft-versus-host disease

e

In vivo

Not defined

miR-296 miR-377

e Kidney podocytes injury

e In vivo/In vitro

IKBKE Not defined

miR-17-5p

Retinal inflammation, hypoxiaeischemia Alcoholic liver disease

e mouse podocyte cell line Rat retinal Müller glial cell line primary hepatocytes and AML-12 cells OSCC cells

In vivo/In vitro

TXNIP

In vivo/In vitro

TXNIP

In vivo/In vitro, patient samples In vitro/In vivo/ patient samples In vitro/In vivo

NLRP3 30 -UTR

Downregulation of the NLRP3 inflammasome and asynuclein Downregulation of the NLRP3 inflammasome; Reduced mRNA level and protein expression of IL-1b, caspase-1 and NLRP3 Downregulation of the NLRP3 inflammasome; Inhibition of IL-1b production Downregulation of NLRP3, ASC and caspase-1; Inhibition of IL-1 and MMP-1 secretion; Downregulation of expression of TXNIP Upregulation of the ERK/NF-kB pathway; Upregulation of the NLRP3 inflammasome; Reduction of Spry1 protein level Inhibition of CXCR4; Downregulation of the TXNIP/NLRP3 inflammasome axis, Reducing of neuropathic pain Down regulating of NLRP3 inflammasome, inhibiting the secretions of IL-18 and IL-1b Up regulating of NLRP3 inflammasome, Inhibiting of the mitochondrial oxygen consumption rate, increasing ROS production, Down-regulating of NLRP3 inflammasome, caspase-1, IL-18, and IL-1b Down-regulating of UCP2, up regulating of NLRP3 inflammasome, increasing activation of Caspase-1 and IL-1b cleavage Down-regulating of NLRP3, caspase-1, ASC, IL-18 and IL-1 Down-regulating of NLRP3 inflammasome, caspase-1, IL-18, and IL-1b up-regulating of NLRP3 inflammasome, caspase-1, P2X7 receptor, ERK-MAP kinase signaling pathway up-regulating of NLRP3 inflammasome Upregulation of the NLRP3 inflammasome; Activation of the p38 MAPK/TXNIP pathway; Downregulation of SOD Downregulation of the NLRP3 inflammasome; Instability of TXNIP mRNA Downregulation of the NLRP3 inflammasome and caspase1; Reduction of pyroptosis Downregulation of the NLRP3 inflammasome

Not defined

In vitro/In vivo

FADD

miR-148a miR-22 miR-302b

Oral squamous cell carcinoma, gastric cancer Gouty arthritis

miR-193b

Cardiac dysfunctions

miR-711

Duchenne muscular dystrophy

THP-1 cells H9C2 cardiomyocyte cell line C2C12 myocytes

IRAK4, EphA2

Downregulation of the NLRP3 inflammasome; Inhibition of IL-1b production Negative regulation of the NLRP3 inflammasome and caspase-1 Downregulation of the NLRP3 inflammasome; Inhibition of IL-1b production

(Jeyabal et al., 2016), (Wang et al., 2017)

(Haneklaus et al., 2012), (Bauernfeind et al., 2012), (Meng et al., 2018), (Wan et al., 2018) Li et al. (2016)

(Sun et al., 2017), (Ning et al., 2017) Pan et al. (2018)

Li et al. (2018a) Xie et al. (2018)

Byeon et al. (2017) Bandyopadhyay et al. (2013)

Xiao et al. (2017) (Bhatt et al., 2016), (Zhang et al., 2018) Chen et al. (2015) Li et al. (2018b) Wang et al. (2015) (Coucha et al., 2017; Lerner et al., 2012),

P. Zamani et al. / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx

Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004

Table 1 The miRNAs that regulate the NLRP3 inflammasome.

Heo et al. (2019) (Feng et al., 2018), (Li et al., 2018c) Ma et al. (2018) Siddeek et al. (2018) Boursereau et al. (2018)

AK1 (janus kinase 1), MMP-13 (matrix metalloproteinase 13), ELAVL1 (ELAV like protein 1), TXNIP (Thioredoxin-interacting protein), RA FLS (rheumatoid arthritis fibroblast-like synoviocytes), Spry1 (sprouty homologue 1), UCP2 (uncoupling protein 2), SOD (superoxide dismutase), IRAK4 (interleukin-1 receptor-associated kinase 4), EphA2 (Eph receptor A2), human monocyte/macrophage cell line (THP1), FADD (Fas-associated protein with death domain).

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Fig. 2.

fibrosis (IPF) (Lasithiotaki et al., 2016). Recently, it was reported that angiotensin II (AngII) promotes miR-21 expression and leads to activation of the NLRP3 inflammasome through the ERK/NF-kB signaling pathway contributing to hepatic fibrogenesis by promoting degradation of the target gene Spry1 (Ling et al., 2012; Ning et al., 2017). This process leads to increased activation of the NLRP3 inflammasome. Overexpression of mir-21 was shown to have a synergistic effect with improved function of AngII treatment. Conversely, downregulation of miR-21 lead to decreased NF-kB translocation and inhibited the protein levels of the NLRP3 inflammasome complex, proIL-1b and caspase-1. These data indicate that miR-21 is involved in the regulation of AngII induced NLRP3 inflammasome activation via the Spry1/ERK/NF-kB pathways (Ning et al., 2017). Up regulation of miR-21 by AngII is an important factor that promoted lung fibroblast collagen synthesis and mediated pulmonary fibrosis by activating the NLRP3 inflammasome through Spry1/ERK/NF-kB pathway. Thus, Spry1 may be a potential targeting gene for miR-21 (Sun et al., 2017).

12. miR-23a Recent reports suggest that miR-23a is highly conserved across different species and contributes to the development of various conditions such as cancer and inflammatory disease (Hatzl et al., 2016; Zhang et al., 2016a). Evidence suggests that miR-23a has a potential modulatory function in the pathogenesis of CNS diseases

with the expression level of miR-23a being decreased in the plasma of patients with MS or acute ischemic stroke (Fenoglio et al., 2013; Jia et al., 2015). miRNA-23a was shown to regulate neuropathic pain via directly targeting of the TXNIP/NLRP3 inflammasome axis (Pan et al., 2018), with the downregulation of miR-23a increasing chemokine CXC receptor 4 (CXCR4) expression in the pSNL-induced neuropathic pain model. Also it was found that miR-23a directly targeted CXCR4 leading to suppression of TXNIP/NLRP3 inflammasome axis, as a direct downstream effector of the miR-23a/ CXCR4 pathway, consequently leading to a reduction in neuropathic pain (Pan et al., 2018).

13. miR-30e miR-30e has been identified as a modulator of the neuroinflammation response in MPTP-induced PD mice model that was capable to directly target NLRP3, which in turn mediated activation of the NLRP3 inflammasome and inflammation. The expression of miR-30e in substantia nigra pars compacta (SNpc) has been shown to be significantly downregulated in PD and may be play an important role in its pathogenesis. They showed that miR-30e acts as a negative regulator of the NLRP3 inflammasome by suppression of NLRP3 expression. MiR-30e upregulation leading to suppression of MPTP-induced an increase of NLRP3, ASC and Caspase-1 expression and also markedly inhibited the secretion of IL-18 and IL-1b, consequently resulting in an improvement of neuronal

Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004

P. Zamani et al. / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx

damage, neuroinflammation and dyskinesia in the MPTP-induced PD mouse model (Li et al., 2018a). 14. miR-33 A recent study reported that a macrophage-specific miR-33 regulated macrophage inflammation that was associated with atherosclerosis, and use of anti-miR-33 treatment inhibited its progression (Ouimet et al., 2015). Recent studies have identified critical roles of miR-33 in regulating of the NLRP3 inflammasome in chronic inflammatory diseases, such as rheumatoid arthritis (RA) with miR-33 upregulating the expression of NLRP3 mRNA and protein in RA-associated monocytes, and consequently enhanced the activation of NLRP3. In addition, it has been show that miR-33 was able to suppress the mitochondrial oxygen consumption rate (OCR) and increase ROS production, which stimulated NLRP3 expression, caspase-1 activity and IL-1b secretion. These data suggest that miR-33 can act as a positive regulator of NLRP3 and may be involved in RA progression (Xie et al., 2018). 15. miR-132 Saturated free fatty acids are important metabolic intermediates that may be synthesized endogenously or obtained through diet and are a major cause of metabolic disturbances. Overload of saturated free fatty acids is toxic and triggers stress signaling pathways, such as the NLRP3 inflammasome, and increase the secretion of IL-1b and IL-18 which play a crucial role in the development of obesity (Legrand-Poels et al., 2014; Wen et al., 2011). miR-132 has been identified as highly upregulated in the human monocytic cell line, THP-1, treated with lipopolysaccharide (LPS), and it may be involved in inhibition of the inflammatory response (Taganov et al., 2006). In addition, miR-132 regulates innate antiviral immunity by targeting p300 (Lagos et al., 2010). It has been shown that miR-132 is involved in regulation of the NLRP3 inflammasome activated with palmitate (PA) in THP-1 cells, with upregulation of both NLRP3 inflammasomes and miR-132 expression following PA treatment. In addition, transfection of PA-treated THP-1 cells with anti-miR-132 significantly enhanced mRNA expression of NLRP3, caspase-1, IL-18, and IL-1b. Moreover, it has been shown that FOXO3 is a potential target of miR-132 that is involved in PA-induced NLRP3 inflammasome regulation: miR-132, by down-regulation of FOXO3, served as a negative feedback regulator of NLRP3 inflammasome activation (Byeon et al., 2017). 16. miR-133 MiR-133 is one of the best characterized myo-miRNAs that is mainly expressed in muscles and is required for proper skeletal and cardiac muscle function and development. There are three genes that encode miR-133 in the human genome: miR-133a-1, miR133a-2 and miR-133b (Yu et al., 2014). Recently, miR-133a mediated regulation of the uncoupling protein 2 (UCP2) expression has been shown to be important in the differentiation of cardiac and skeletal muscle (Chen et al., 2009). UCP2 is a member of the superfamily of uncoupling proteins located in the inner membrane of mitochondria, and it plays a pivotal role in regulation of ATP synthesis and ROS production in the mitochondria (Ball et al., 2011; Ledesma et al., 2002). UCP2 is also widely expressed in different components of the immune system, such as the lungs, spleen and isolated macrophages (Fleury et al., 1997). A recent study showed that UCP2 acts as a negative regulator of mitochondrial ROS generation and induces an anti-inflammatory response that might be mediated through the p38/ERK1/2 MAPK signaling pathway (that is involved in induction of proinflammatory cytokines) (Ball et al., 2011). A

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study conducted by Bandyopadhyay and co-workers reported that miR-133a-1 is involved in the regulation of the NLRP3 inflammasome and IL-1b secretion. They showed that overexpression of miR133a-1 enhanced activation of Caspase-1 and also increased processing and secretion of IL-1b. In addition, miR-133a-1-mediated down-regulation of UCP2. THP1 cells transfected by UCP2 siRNA exhibited a significant increase in activation of Caspase-1 and secretion of IL-1b in response to H2O2. Therefore, it appears that UCP2 may act as a negative regulator of inflammasome activation (Bandyopadhyay et al., 2013). Considerable evidence indicates that miR-133b may serve as a biomarker to diagnose and characterize inflammation (Xu et al., 2014). The serum concentration of miR133b in allergic rhinitis (AR) patients was significantly downregulated, and miR-133b expression was reduced, in the plasma of patients with inflammatory myopathy (Georgantas et al., 2014; Panganiban et al., 2016). MiR-133b has low expression in the nasal mucosa of the AR mouse model and this may relate to the proallergic properties of AR. Furthermore, intranasal administration of miR-133b agomir ameliorated allergic symptoms in AR mice. MiR-133b also directly suppressed the NLRP3 inflammasome and decreased the expression of NLRP3, caspase-1, ASC, IL-18 and IL-1. Thereby, miR-133b served as a negative regulator of NLRP3 expression by binding to the 3’ untranslated region of NLRP3 and inhibiting its activation (Xiao et al., 2017). Recently, Yu and coworkers have reported that LncRNA MALAT1 (long noncoding RNA metastasis associated lung adenocarcinoma transcript 1) sponges miR-133 may serve as a potential regulator to promote NLRP3 inflammasome expression in ischemia/reperfusion-injured heart. They proposed that lncRNA MALAT1 contained a miR-133 expression functional target site that can act as a competing endogenous RNA to reduce miR-133 action and enhance NLRP3 inflammasome expression in ischemia-reperfusion injured heart (Yu et al., 2018). 17. miR-146 Inflammation is one of the critical factors in development and progression of diabetic complications, including diabetic nelez et al., 2011; Shikata and phropathy (DN) (Navarro-Gonza Makino, 2013). Recent data supports the role of miRNAs as important regulators of DN (Kato and Natarajan, 2012; Lorenzen et al., 2011). Previous studies showed that miR-146a is a negativefeedback regulator in the inflammatory signaling pathway and directly downregulates the production of pro-inflammatory cytokines by targeting TNF receptor associated factor 6 (TRAF6) and IL-1 receptor associated kinase (IRAK1) (Li et al., 2013; Park et al., 2015). The miR-146a promoter is a NF-kB dependent gene that is critical for the transcriptional activation of the miR146a gene in response to inflammatory stimuli such as IL-1b, LPS and TNF-a (Boldin and Baltimore, 2012; Taganov et al., 2006). Overexpression of miR146a has been shown to reduce the expression of IL-1b, TNF-a, and IL-8 during the acute inflammatory response to monosodium urate (MSU) crystals (Dalbeth et al., 2015). MiR-146a has an antiinflammatory role in the pathogenesis of DN and miR-146a deficiency leads to a marked increase in the severity of DN and augmentation of proinflammatory cytokines and profibrotic gene expression during DN. Gene expression analysis showed that the expression levels of NLRP3, IL-1b and IL-18 were significantly increased in the macrophages of diabetic miR-146a/- mice. In addition, caspase-1 has a higher activity in peritoneal macrophages. These results support the concept that miR-146a might have antiinflammatory effects, and miR-146a deficiency leads to increased activation of the NLRP3 inflammasome and enhanced production of IL-1b and IL-18 which, in turn, enhanced inflammatory responses (Bhatt et al., 2016). A recent study demonstrated that miR-146a

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regulated gouty arthritis by dysregulation of TRAF6, IRAK1 and the NALP3 inflammasome. Deficiency of miR-146a promoted the proinflammatory cytokines, IL-1b and TNF-a, and found that the gene expression of NALP3, ASC and caspase-1 were significantly overexpressed in mice with miR-146a deficiency (Zhang et al., 2018). Accordingly, miR-146a may serve as a negative regulator of inflammatory and immune responses through downregulation of TRAK6/IRAK1 and NLRP3 inflammasome function. 18. miR-155 Work by Ceppi et al. demonstrated that miR-155 negatively regulated the IL-1 signaling pathway in activated human monocyte-derived DC and downregulated inflammatory cytokine production in response to microbial stimuli. Hence, the TLR/IL-1b inflammatory pathway may serve as a target of miR-155 (Ceppi et al., 2009). Moreover, a previous study showed that miR-155 is a proinflammatory regulator that decreased expression levels of SH2-containing inositol-50 -phosphatase 1 (SHIP-1) and indirectly promoted the production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-a) and IL-1b (Jin et al., 2014). The NLRP3 inflammasome plays an important regulatory function in graftversus-host disease (GvHD) (Jankovic et al., 2013). IL-1 and TNF-a are principal mediators and central cytokines in the promotion of acute GVHD (Hill et al., 1999). MiR-155 is involved in the regulation of acute GVHD and plays a key role in GVHD induction. MiR-155 expression is upregulated in the donor T-cell compartment of mice developing acute GVHD and is required for the development of acute GVHD (Ranganathan et al., 2012). MiR-155 deficiency reduced serum levels of proinflammatory cytokines, leading to improved survival and reduced severity of GVHD. Global gene expression analysis in the miR-155/ DCs revealed downregulation of multiple proinflammatory purinergic receptors, such as the P2X7 receptor, that play important roles in NLRP3 inflammasome activation. Reduced expression of P2X7 impaired migration toward ATP. Therefore, it appears that a functional interaction exists between miR-155 and P2X7. Moreover, microarray analysis demonstrated the expression of the ERK-MAP kinase signaling pathway, that has a critical role in inflammasome activation, was dysregulated and significantly reduced in miR-155/ DCs compared with wild type DCs. Also, the expression level of the NLRP3 inflammasome and caspase-1 were markedly reduced in miR-155/ DCs. Taken together, these findings suggest that miR155 was able to overexpress both the NLRP3 inflammasome and caspase-1, and promote inflammation (Chen et al., 2015). 19. miR-296 MiR-296 is a family of microRNA precursors found in mammals, and especially in humans. Generally, miR-296 is the precursor of miRNA-296-5p, derived from the 50 arm, and miRNA-296-3p, derived from the 30 arm. Recent studies suggest that miR-296 plays important roles in the regulation of the inflammatory response, angiogenesis, cholesterol metabolism, hypertension, cellular proliferation and apoptosis (Li et al., 2018b). MiR-296 plays a crucial role in regulating the NF-kB signaling pathway. Also, miR296, through suppression of NumbL and activation of NF-kB, plays an inflammatory role in lung cancer (Vaira et al., 2013). The inhibitor of kB kinase epsilon (IKBKE) might be a regulator and inhibit chronic inflammation during metabolic disease and atherosclerosis, and may play an important role in inhibition of the NLRP3 inflammasome in macrophages and the reduced secretion of IL-1b (Patel et al., 2015). Robson et al. found that miR-296-5p targeted IKBKE (Robson et al., 2012). Thus, it is possible that miR-296-5p, through directly targeting of IKBKE, causes activation of the

NLRP3 inflammasome and promotes inflammation in atherosclerotic disease (Li et al., 2018b). 20. miR-377 Overexpression of miR-377 promotes oxidative stress by reducing superoxide dismutase 1 (SOD1) and SOD2, and indirectly leads to increased production of the fibronectin protein in diabetic nephropathy (Wang et al., 2008). Recent studies by Wang et al. reported that miR-377 plays a key role in response to oxidative stress through the p38 MAPK/TXNIP/NLRP3 inflammasome pathway and can act as a biomarker of oxidative stress in the renal cortex of the fructose-induced metabolic syndrome rat model with podocyte injury (Wang et al., 2015). MiRNA expression profiling displayed miR-377 overexpression in fructose-fed rats with podocyte injury. In addition, the kidney glomerular SOD1 and SOD2 protein levels were significantly reduced, demonstrating that miR377 overexpression led to SOD downregulation. Oxidative stress and ROS overproduction promoted phosphorylation and activation of p38 MAPK that enhanced TXNIP protein levels in kidney glomeruli of fructose-fed rats. These results demonstrate that overexpression of miR-377, via activation of the p38 MAPK/TXNIP pathway, led to inhibition of SOD and suppression of oxidative stress in fructose-exposed differentiated podocytes. Expression levels of NLRP3, ASC, caspase-1 and IL-1b protein were elevated in fructose-fed rats. Treatment with pterostilbene and allopurinol downregulated miR-377/TXNIP overexpression, completely suppressed the activation of the NLRP3 inflammasome, reduced IL-1b levels and prevented glomerular podocyte inflammation (Wang et al., 2015). 21. miR-17 Bioinformatic analysis of the TXNIP mRNA revealed two conserved binding sites with high confidence matches for binding miR-17-5p within its 30 -UTR. A recent study indicated that during stress condition, such as endoplasmic-reticulum-stress (ER stress), the levels of TXNIP mRNA stability increased while the levels of TXNIP destabilizing miR-17-5p rapidly decreased (Lerner et al., 2012). The endoplasmic reticulum (ER) is the main organelle for folding and maturation of proteins to their native conformations (Gething and Sambrook, 1990). Inability to correctly execute protein folding leads to “ER stress,” and causes accumulation of unfolded proteins within the ER, leading to activation of IRE1a (inositol requiring enzyme 1a), an ER transmembrane kinaseendoribonuclease (RNase) (Harding et al., 1999; Tirasophon et al., 1998). IRE1a promotes adaptation and triggers programmed cell death by regulating proapoptotic proteins through miRNA biogenesis in response to ER stress signaling (Upton et al., 2012). ER-stress plays an integral role in the pathogenesis and progression of various chronic diseases, including cardiovascular pathology and diabetic retinopathy (Chistiakov et al., 2014; Ma et al., 2014). Recent work has shown that hyperactivation of IRE1a, induced by ER stress signaling, increases TXNIP at the mRNA and protein levels and reduced levels of miR-17-5p which, in turn, leads to activation of the NLRP3 inflammasome and caspase-1 that promote IL-1b secretion (Lerner et al., 2012). Recent studies by Coucha et al. reported that ER stress induced by high fat diet upregulates expression of TXNIP and decreased miR-17-5p expression in Müller cells, leading to retinal inflammation. These findings suggest that IRE1a is directly activated by ER-stress, leading to dysregulation and degeneration of miR-17-5p which subsequently triggers TXNIP expression by increasing TXNIP mRNA stability and activation of the NLRP3 inflammasome (Coucha et al., 2017). A previous study showed that the TXNIP mRNA and protein levels were

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downregulated by administration of miR-17-5p mimic, leading to inhibition of the NLRP3 inflammasome. By contrast, administration of anti-miR-17-5p inhibitor upregulated TXNIP expression and NLRP3 inflammasome activation in the neonatal hypoxiaeischemia (HI) model (Chen et al., 2018). Taken together, these data demonstrated that miR-17-5p acts as a posttranscriptional regulator for TXNIP expression and suppressed expression of the NLRP3 inflammasome, thus alleviating inflammatory damage.

NLRP3 inflammasome (Feng et al., 2018). Li et al. reported that the expression of NLRP3 was significantly upregulated in gastric cancer, thus promoting NLRP3 inflammasome function and enhancing IL1b secretion in macrophages and leading to cell proliferation and gastric cancer progression. The findings of Li et al. show that miR22 serves as a negative modulator of NLRP3 that directly targets NLRP3 and reduces its oncogenic effects in vitro and in vivo (Li et al., 2018c).

22. miR-148

24. miR-302

Inflammation plays an important role in the development and pathogenesis of alcoholic liver disease (ALD) and is the major driving force during ALD progression (Szabo and Csak, 2012). Liver inflammation drives the progression of steatosis to steatohepatitis, fibrosis and cirrhosis, and ultimately leading to hepatocellular carcinoma. Excessive alcohol consumption and detoxification processes promote hepatocyte dysfunction through release of uric acid and extracellular ATP, production of ROS and mitochondrial dysfunction; this leads to activation of multiple inflammatory pathways, thereby increasing levels of TNF-a, IL-1 and IL-1b, and finally sensitizing hepatocytes to inflammatory cytokines and death during the progression of liver disease (Barnes et al., 2014; Geng et al., 2015; Iracheta-Vellve et al., 2015; Khoruts et al., 1991; ~ ana et al., 2002; Wu and Cederbaum, 2003). In recent years, it Min has been shown that a set of miRNAs are dysregulated during ALD (Bala et al., 2011; Blaya et al., 2016; Yin et al., 2015; Zhang et al., 2010). Heo et al. reported that miR-148a levels were substantially downregulated in patients with alcoholic hepatitis (AH) and in AlD animal models; downregulation of miR-148a is correlated with TXNIP overexpression in hepatocytes (Heo et al., 2019). Heo and colleagues reported that FoxO1 levels were highly associated with miR-148a levels. FoxO1 transcriptionally controls miR-148a expression and enhanced the levels of both the primary and the mature forms of miR-148a. Expression of TXNIP, NLRP3, ASC, active caspase-1 and IL-1b were significantly upregulated in the alcoholinduced hepatocyte injury animal model and also following ethanol treatment of primary hepatocytes or AML-12 cells. MiR148a transfection attenuated the expression of TXNIP and inhibited activation of NLRP3 and caspase-1-mediated pyroptosis. These events were consistent with the results obtained by TXNIP knockdown. Collectively, these findings indicate that miR-148a directly inhibits TXNIP expression and prevents NLRP3 inflammasome activation (Heo et al., 2019).

Recently, miR-302b has been shown to be a novel inflammatory regulator that is induced by TLR2 and TLR4 through ERK-p38-NF-kB signaling in respiratory bacterial infections (Zhou et al., 2014). Ma et al. showed that miR-302b is highly expressed in both THP-1 cells and in animal models treated with monosodium urate (MSU) crystals. Overexpression of miR-302b regulated NF-kB and caspase1 signaling, leading to significantly repressed protein and mRNA levels of IL-1b in cells treated with the MSU crystals. Bioinformatic analysis predicted that IRAK4 and Eph receptor A2 (EphA2) were the potential targets of miR-302b, and this was then evaluated by genetic approaches including luciferase constructs containing mutated 30 UTR of IRAK4 and EphA2 miR-302b. Results indicated that miR-302b has an inhibitory function on IRAK4 and EphA2 by binding to their 30 -UTR regions. Further analysis, by silencing IRAK4 and EphA2 in the THP-1 cells, indicated that the protein expression levels of IL-1b and caspase-1 were markedly reduced in THP-1 cells transfected with IRAK4 or EphA2 siRNA. Collectively, these findings indicate that miR-302b, by targeting IRAK4 and EphA2, leads to a downregulation of activation of NF-kB and reduced activation of the NLRP3 inflammasome which subsequently inhibits caspase-1mediated IL-1b protein maturation (Ma et al., 2018).

23. miR-22 Accumulating evidence indicates that miR-22 is an important regulator of tumorigenesis and is involved in various cellular processes related to the development of cancer (Damavandi et al., 2016; Jiang et al., 2016; Yang et al., 2015; Zhang et al., 2016b). MiR-22, a cancer-related miRNA that acts as a tumor suppressor, is down-regulated in several tumor types, including liver, breast, and gastric cancer as well as acute myeloid leukemia (Damavandi et al., 2016; Jiang et al., 2016; Yang et al., 2015). MiR-22 is downregulated in oral squamous cell carcinoma (OSCC) tissues. Overexpression of miR-22 inhibits cell growth, migration and invasion by suppressing NLRP3 (Feng et al., 2018). Bioinformatics analysis indicated that NLRP3 was targeted by miR-22 and that the target site was located in the 30 -UTR. In vitro in cells co-transfected with miR-22 mimic and NLRP3 30 -UTR, the NLRP3 30 -UTR reporter gene was markedly decreased, confirming that the NLRP3 30 -UTR is a direct target of miR-22. Overexpression of miR-22 downregulated NLRP3 expression, whereas anti-miR-22 upregulated the expression of NLRP3 in SCC25 cells. Therefore, miR- 22 acts as negative regulator of the

25. miR-193 The organization and the sequences of the miR-193b-365 cluster, which is composed of two paralogs, are highly conserved among vertebrates and were first identified in multiple myeloma (Unno et al., 2009). MiR-193a is upregulated in multiple myeloma and has growth-inhibitory activity via repression of the expression and functions of c-kit in myeloid leukemogenesis; thus it serves as a tumor suppressor miRNA (Gao et al., 2011). In addition, miR-193b regulates inflammation in human adipose tissue through effects on chemokine (CeC motif) ligand 2 (CCL2) production from adipocytes and macrophages via targeting of V-ets erythroblastosis virus E26 oncogene homologue 1 (ETS1) and MYC-associated factor X (MAX) (Arner et al., 2012). Furthermore, it was reported the NFkB is involved in the regulation of miR-193b expression (VentoTormo et al., 2014). Siddeek et al. reported a novel role for miR193b in cardiomyocyte function through regulation of NLRP3 (Siddeek et al., 2018). By using in silico analysis with MiRTarBase, they showed that miR-193b served as a regulator of NLRP3 and ETS1. Then, they evaluated the regulation of the NLRP3 inflammasome by miR-193b in the H9C2 cardiomyocyte cell line transfected with pre-miR-193b: transfection with pre-miR-193b decreased the protein levels of NLRP3 and caspase-1, but the levels of TXNIP and IL-1 b protein were unaffected. Collectively, these findings suggest that miR-193b might serve as a negative regulator for the NLRP3 inflammasome but further investigation is warranted (Siddeek et al., 2018). 26. miR-711 Adiponectin is an anti-inflammatory hormone secreted by adipocytes that acts as a major mediator of inflammatory and

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immunity responses in various tissues, including skeletal muscle (Luo and Liu, 2016; Ouchi and Walsh, 2007). Recently, it has been shown that the anti-inflammatory action of adiponectin is mediated by miR-711. MiR-711, which is overexpressed by adiponectin, inhibits several components of the TLR4 signaling pathway, such as Fas-associated protein with death domain (FADD), which in turn cause repression of NF-kB activity and downstream proinflammatory cytokines, especially NLRP3 inflammasome associated cytokines (Boursereau et al., 2017). Boursereau et al. found that NLRP3 is expressed in skeletal muscle and could play a pivotal role in muscle inflammation; they also found that adiponectin was able to downregulate NLRP3 through miR-711. Gene silencing of FADD, that acts as one of the target genes of miR-711, is associated with priming and activation of the NLRP3 inflammasome (Gurung et al., 2014) and reduced expression of NLRP3 mRNA and protein in inflamed muscle cells. Adiponectin downregulates NLRP3 expression via miR-711 and reduced mature IL-1b, IL-18 and caspase-1 levels. Taken together, these finding indicate that, although NLRP3 is not a direct target of miR-711, miR-711 was able to indirectly suppress NLRP3 expression and transcriptional priming through inhibition of NF-kB and FADD (Boursereau et al., 2018). 27. Conclusion The NLRP3 inflammasome is a critical player in the induction of inflammation and initiation of host immune responses, which can be activated by different DAMPs and PAMPs. The indispensable role of the NLRP3 inflammasome has been widely investigated in various inflammatory diseases, such as atherosclerosis, chronic heart failure, Alzheimer disease and multiple sclerosis. Emerging evidence demonstrates that post-transcriptional regulation by miRNAs is involved in the pathophysiological processes associated with the NLRP3 inflammasome. These data provide a link between NLRP3 inflammasome regulation and miRNAs, thus providing insight into the potential regulatory effects of miRNAs and the NLRP3 inflammasome and opening up novel potential therapeutic avenues for disease modulation. Declaration of interests None. Funding No funding was received for the preparation of this review. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.pbiomolbio.2019.05.004. References Alexander, M., O'connell, R.M., 2015. Noncoding RNAs and chronic inflammation: micro-managing the fire within. Bioessays 37, 1005e1015. Altaf, A., Qu, P., Zhao, Y., Wang, H., Lou, D., Niu, N., 2015. NLRP3 inflammasome in peripheral blood monocytes of acute coronary syndrome patients and its relationship with statins. Coron. Artery Dis. 26, 409e421. , A., et al., 2012. Adipose tissue microRNAs as regulators Arner, E., Mejhert, N., Kulyte of CCL2 production in human obesity. Diabetes 61, 1986e1993. Artlett, C.M., 2012. Suppl 1: the role of the NLRP3 inflammasome in fibrosis. Open Rheumatol. J. 6, 80. Bala, S., Marcos, M., Kodys, K., et al., 2011. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor a (TNFa) production via increased mRNA half-life in alcoholic liver disease. J. Biol. Chem. 286, 1436e1444. Ball, W.B., Kar, S., Mukherjee, M., Chande, A.G., Mukhopadhyaya, R., Das, P.K., 2011. Uncoupling protein 2 negatively regulates mitochondrial reactive oxygen

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Please cite this article as: Zamani, P et al., MicroRNAs as important regulators of the NLRP3 inflammasome, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.05.004