Beneficial Properties of Phytochemicals on NLRP3 Inflammasome

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Beneficial properties of phytochemicals on NLRP3 inflammasome-mediated gout and complication Jhih-Jia Jhang, Jia-Hong Lin, and Gow-Chin Yen J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b05113 • Publication Date (Web): 02 Jan 2018 Downloaded from http://pubs.acs.org on January 3, 2018

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Journal of Agricultural and Food Chemistry

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Beneficial properties of phytochemicals on NLRP3

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inflammasome-mediated gout and complication

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Jhih-Jia Jhang†, Jia-Hong Lin†, and Gow-Chin Yen †,‡,*

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†

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University, 145 Xingda Road, Taichung 40227, Taiwan

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‡

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Xingda Road, Taichung 40227, Taiwan

Department of Food Science and Biotechnology, National Chung Hsing

Graduate Institute of Food Safety, National Chung Hsing University, 145

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*Author to whom correspondence should be addressed.

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Tel: 886-4-2287-9755, Fax: 886-4-2285-4378,

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E-Mail: [email protected]

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Keywords: gout; monosodium urate; IL-1β; NLRP3; phytochemicals

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Abbreviations:

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CARD, caspase recruitment domains; DAMPs danger-associated molecular patterns;

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EGCG, epigallocatechin gallate; IL-1β, interleukin-1β; LPS, lipopolysaccharide; LRR,

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leucine-rich repeat; MSU, monosodium urate; MtROS, mitochondrial reactive oxygen

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species; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization

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domain-like receptor containing pyrin domain 3; NLRs, nucleotide-binding domain

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leucine-rich

repeat

(LRR)-containing

receptors;

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ACS Paragon Plus Environment

NSAIDs,

nonsteroidal


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anti-inflammatory drugs; PAMPs, pathogen-associated molecular patterns; PGE2,

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prostaglandin E2; PRRs, pattern recognition receptors; ROS, reactive oxygen species;

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STZ, streptomycin; TNF-α, tumor necrosis factor-α; TRX, thioredoxin; TXNIP,

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thioredoxin interaction protein

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Abstract

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Gouty arthritis is characterized by the precipitation of monosodium urate (MSU)

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crystals in the joint. Pro-inflammatory cytokine IL-1β is a critical manifestation in

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response to MSU crystals attack. IL-1β secretion is dependent on the

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nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3

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(NLRP3) inflammasome. Abnormal activation of the NLRP inflammasome is related

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to cellular oxidative stress. However, recent studies have illustrated that

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phytochemicals with potent antioxidant activity exert inhibitory effects on NLRP3

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inflammasome-mediated diseases. This review focuses on the current findings of

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studies on the NLRP3 inflammasome and the proposed mechanisms that MSU

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crystals trigger inflammation via activation of the NLRP3 inflammasome. We also

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summarized the potential use of phytochemicals on NLRP3 inflammasome-mediated

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diseases, suggesting that phytochemicals can further prevent acute gout attack.

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INTRODUCTION

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Gout is usually characterized as an elevation of serum uric acid and

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crystallization of monosodium urate (MSU) 1. MSU crystals are needle-shaped and

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aggregate as tophi in and around joints, soft tissues, and various organs 2. The

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deposition of MSU crystals in joints further triggers inflammatory responses, known

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as gouty inflammation. Gouty inflammation can occur in bursae, tendons, and joints.

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The first gout flare predominately occurs in the large joint of the big toe (the first

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metatarsophalangeal). In addition, foot, knee, elbow, and hand are common attack

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locations 1-2.

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MSU crystals induces inflammation by activation of the complement system and

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recruits mast cells, neutrophils, and monocyte cells that infiltrate the joint tissue,

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causing cartilage and synovial tissue damage 1-2. In addition, the secretion of IL-1β, a

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pro-inflammatory cytokine, is the main clinical manifestation of an early gout attack

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3-4

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complex called the nucleotide-binding oligomerization domain-like receptor pyrin

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domain containing 3 (NLRP3, also known as NALP3 or cryopyrin) inflammasome 5.

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Redox signaling molecules, such as reactive oxygen species (ROS), mediate NLRP3

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inflammasome activation, while ROS inhibitors suppress NLRP3 inflammasome-

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mediated inflammation

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inflammasome activation

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supplementation of vitamin C can decrease the risk of gout

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consumption and cherry extracts can decrease risk of recurrent gout attacks

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pre-clinical study first demonstrated that the phytochemical epigallocatechin gallate

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(EGCG) is a ROS scavenger as well as an inflammasome suppressor 13. In this review,

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we attempted to elucidate the cellular and molecular mechanisms of the

. MSU crystals trigger the maturation of IL-1β via the recruitment of a cytosolic

, indicating the vital role of oxidative stress on . Previous studies showed that daily coffee intake and

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10-11

, and cherry fruit 12

. A

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inflammasome activation in gout. In addition, previous studies have illustrated that

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phytochemicals with antioxidant properties can reduce inflammatory responses via the

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modulation of inflammasome activity

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promoting anti-inflammasome activity is also discussed.

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. The usefulness of phytochemicals for

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HYPERURICEMIA AND GOUT Uric acid is a metabolite of purine metabolism through xanthine oxidase enzyme 15

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converting hypoxanthine and xanthine

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which converts urate into the more soluble and easily excreted allantoin 15. The lack

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of a functional uricase gene in Homo sapiens during evolution has resulted in the

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accumulation of urate levels in blood. Approximately one-third of the urate level

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inside the body is eliminated through the gastrointestinal tract, with the remainder

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excreted in the urine. The levels of normal plasma urate are between 200 and 410

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µmol/L (3.3 to 6.9 mg/dL), and urate has a maximum solubility of 420 µmol/L (7

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mg/dL), approximately

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which is defined by blood urate level over 7 mg/dL 17. Hyperuricemia has a primary

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role in complications, such as gout, hypertension, chronic kidney disease, and

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metabolic syndrome 17-18.

. Most mammalian species express uricase,

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. Over-production of urate is the cause of hyperuricemia,

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Gout attack is triggered by the precipitation of MSU crystals in the joints. The

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presence of MSU crystals is characteristic of gouty arthritis 19. A study demonstrated

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that large needle-shape crystals of urate specifically existed in the synovial fluid in

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gouty patients, which is different from other types of arthritis, such as rheumatic

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arthritis patients and osteoarthritis

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populations have a higher prevalence of gout compared to other areas of the world 20.

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Particularly, the prevalence of gout in Oceanic populations within ethnic groups, such

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. People in developed countries and in Oceanic

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as Taiwanese aboriginals and Maori, is over 10%. From seven representative

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countries, the age-specific prevalence of gout is similar in the USA, New Zealand,

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UK, and Netherlands. Taiwan has a higher prevalence of gout in all age strata,

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whereas South Korea has the lowest age-specific prevalence

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was observed from Nutrition and Health Surveys in Taiwan (NAHSIT) 1993-1996 to

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NAHSIT 2005-2008 in gout prevalence (4.74%→8.21% in men, p

Beneficial Properties of Phytochemicals on NLRP3 Inflammasome

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