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Anti-NLRP3 Inflammasome Natural Compounds: an Update

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Anti-NLRP3 Inflammasome Natural Compounds: an Update biomedicines Review Anti-NLRP3 Inflammasome Natural Compounds: An Update Baolong Liu and Jiujiu Yu * Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; [email protected] * Correspondence: [email protected] Abstract: The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex that recognizes various danger or stress signals from pathogens, the host, and the environment, leading to activation of caspase-1 and inducing inflammatory responses. This pro-inflammatory protein complex plays critical roles in pathogenesis of a wide range of diseases including neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Therefore, intensive efforts have been devoted to understanding its activation mechanisms and to searching for its specific inhibitors. Approximately forty natural compounds with anti-NLRP3 inflammasome properties have been identified. Here, we provide an update about new natural compounds that have been identified within the last three years to inhibit the NLRP3 inflammasome and offer an overview of the underlying molecular mechanisms of their anti-NLRP3 inflammasome activities. Keywords: NLRP3 inflammasome; natural compounds; inflammatory diseases; medicinal herbs 1. Introduction Citation: Liu, B.; Yu, J. Anti-NLRP3 The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin Inflammasome Natural Compounds: domain containing 3 (NLRP3) inflammasome is a cytosolic protein complex in the innate im- An Update. Biomedicines 2021, 9, 136. mune cells. It is composed of NLRP3, apoptotic speck protein containing a caspase recruit- https://doi.org/10.3390/ ment domain (ASC), and caspase-1 [1,2]. In response to a variety of pathogen-associated biomedicines9020136 molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the sen- sor NLRP3 recruits the adaptor ASC, which further recruits the effector caspase-1 to form Academic Editor: Concettina the inflammasome complex. Caspase-1 autocleaves itself to generate the active enzyme, La Motta which cleaves pro-interleukin (IL)-1β and pro-IL-18 to generate the mature cytokines IL-1β Received: 23 December 2020 and IL-18. Active caspase-1 also cleaves gasdermin D to induce pyroptotic cell death to Accepted: 23 January 2021 amplify the inflammatory responses [3,4]. Published: 1 February 2021 The NLRP3 inflammasome has become an attractive therapeutic target because grow- ing evidence has shown that its inappropriate activation is involved in the pathogenesis of Publisher’s Note: MDPI stays neutral many complex diseases, such as Alzheimer’s disease, type 2 diabetes, and gout [5,6]. In with regard to jurisdictional claims in clinical practice, protein-based therapies that block the action of IL-1β have been tested in published maps and institutional affil- patients. For example, injection of anakinra, a recombinant human IL-1 receptor antagonist iations. protein, in diabetic patients suppressed systemic inflammation, lowered plasma glucose, and improved β-cell secretory function [7,8]. Rilonacept, a soluble decoy IL-1 receptor, reduced inflammatory markers, pain, and swelling in gout patients in clinical trials [9]. While these protein-based therapies are promising, they are costly, require frequent injec- Copyright: © 2021 by the authors. tion, and block only one downstream pathway of the NLRP3 inflammasome. Therefore, Licensee MDPI, Basel, Switzerland. it is highly desirable to identify other potential therapeutic interventions that target the This article is an open access article NLRP3 inflammasome. distributed under the terms and Remarkably, many natural compounds or nutrient molecules have been shown to conditions of the Creative Commons suppress activation of the NLRP3 inflammasome. Two recent reviews [10,11] provide a Attribution (CC BY) license (https:// comprehensive overview of these natural products. In this review, we will (1) introduce the creativecommons.org/licenses/by/ background information about NLRP3 inflammasome activation and its involvement in 4.0/). Biomedicines 2021, 9, 136. https://doi.org/10.3390/biomedicines9020136 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 19 the background information about NLRP3 inflammasome activation and its involvement in diseases, and (2) provide an update of natural compounds with anti-NLRP3 inflam- masome functions that have been identified within the last three years. 2. NLRP3 Inflammasome and Its Involvement in Diseases 2.1. Activation of the NLRP3 Inflammasome The molecular mechanisms of NLRP3 inflammasome activation have been reviewed in depth [12–16]. Here, we summarize general principles of NLRP3 inflammasome acti- Biomedicines 2021, 9, 136vation (Figure 1) to provide background knowledge about how natural compounds target 2 of 19 this key pro-inflammatory protein complex. Although the precise molecular mechanisms of NLRP3 inflammasome activation are not fully understood, it is generally accepted that NLRP3 inflammasome activation re- quires an initialdiseases, priming and (2) step provide followed an update by an activation of natural compoundsstep (Figure with1) [12,13]. anti-NLRP3 A priming inflammasome signal, suchfunctions as lipopolysaccharide that have been identified(LPS), activates within nuclear the last threefactor years.kappa-light-chain-en- hancer of activated2. NLRP3 B Inflammasome cells (NF-κB) signaling, and Its Involvement leading to increased in Diseases expression of the Il1b and Nlrp3 genes. The priming signal also induces the deubiquitination of NLRP3 protein, 2.1. Activation of the NLRP3 Inflammasome which is a prerequisite for optimal activation of the NLRP3 inflammasome [17–19]. Acti- vating signals forThe the molecular NLRP3 mechanismsinflammasome of NLRP3include inflammasome a variety of molecules activation with have diverse been reviewed in depth [12–16]. Here, we summarize general principles of NLRP3 inflammasome activation and un-related chemical structures. For example, ATP, nigericin, alum, free fatty acids (Figure1) to provide background knowledge about how natural compounds target this (FFAs), cholesterol crystals, or monosodium urate (MSU) crystals can serve as an activat- key pro-inflammatory protein complex. ing signal to promote the assembly and formation of the NLRP3 inflammasome [12,13]. Activating signals (ATP, FFA, MSU) K efflux Priming signals Ca mobilization (LPS) mtROS Trans-golgi NF-kB mtDNA disassembly activation Cardiolipin Lysosomal Nlrp3 damage Il1b NLRP3 inflammasome NEK7 NLRP3 Cleaved active ASC caspase-1 PYD NACHT LRR NLRP3 Caspase-1 Pro-IL-1! IL-1! ASC Pro-IL-18 Gasdermin D IL-18 Caspase-1 Pyroptosis CARD Caspase Figure 1. MolecularFigure mechanisms 1. Molecular of mechanisms NLRP3 inflammasome of NLRP3 inflammasome activation. The activation. NLRP3 inflammasome The NLRP3 inflammasome is activated throughis an initial primingactivated step followed through by an an initial activating priming step. step The followed priming by signals,an activating such asstep. lipopolysaccharide The priming signals, (LPS), such activate NF-κB signaling,as which lipopolysaccharide induces transcription (LPS), activate of the Nlrp3 NF-κandB signaling,Il1b genes. which The activatinginduces transcription signals, such of as the ATP, Nlrp3 nigericin, and free Il1b genes. The activating signals, such as ATP, nigericin, free fatty acids (FFAs), monosodium urate fatty acids (FFAs), monosodium urate (MSU) or cholesterol crystals, can trigger a series of cellular events, which typically (MSU) or cholesterol crystals, can trigger a series of cellular events, which typically include potas- include potassium efflux, calcium mobilization, mitochondrial (mt) damage (leading to release of reactive oxygen species sium efflux, calcium mobilization, mitochondrial (mt) damage (leading to release of reactive oxygen (ROS), DNA, andspecies cardiolipin), (ROS), trans-GolgiDNA, and cardiolipin), disassembly, trans-Golg and lysosomali disassembly, rupture. Theseand lysosomal upstream rupture. cellular eventsThese up- converge on the NLRP3 protein,stream causingcellular itsevents conformational converge on change the NLRP3 and leadingprotein, tocausing oligomerization its conformational of NLRP3 change with theand assistance lead- of NEK7 protein. Oligomerizeding to oligomerization NLRP3 recruitsof NLRP3 ASC, with which the assistance further recruits of NEK7 caspase-1, protein. Oligomerized to form the NLRP3 NLRP3 inflammasome recruits complex. Caspase-1ASC, autocleaveswhich further itself recruits to generate caspase-1, the to active form enzyme,the NLRP3 which inflammasome cleaves pro-IL-1 complex.β and Caspase-1 pro-IL-18 auto- to release mature cytokines.cleaves Active itself caspase-1 to generate also cleavesthe active gasdermin enzyme, Dwhich to induce cleaves pyroptosis. pro-IL-1β Bothand pro-IL-18 cytokine releaseto release and mature pyropototic cell death triggercytokines. inflammation. Active caspase-1 also cleaves gasdermin D to induce pyroptosis. Both cytokine release and pyropototic cell death trigger inflammation. Although the precise molecular mechanisms of NLRP3 inflammasome activation are not fully understood, it is generally accepted that NLRP3 inflammasome activation requires an initial priming step followed by an activation step (Figure1)[ 12,13]. A priming signal, such as lipopolysaccharide (LPS), activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling,
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