title: Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout.
abstract: Gouty arthritis is caused by the deposition of uric acid crystals, which induce the activation of NOD-like receptor family, pyrin domain containing 3(NLRP3) inflammasome. The NLRP3 inflammasome, composed of NLRP3, the adaptor protein ASC, and caspase-1, is closely linked to the pathogenesis of various metabolic diseases including gouty arthritis. We investigated whether an orally administrable inhibitor of NLRP3 inflammasome was effective for alleviating the pathological symptoms of gouty arthritis and what was the underlying mechanism. In primary mouse macrophages, caffeic acid phenethyl ester(CAPE) blocked caspase-1 activation and IL-1β production induced by MSU crystals, showing that CAPE suppresses NLRP3 inflammasome activation. In mouse gouty arthritis models, oral administration of CAPE suppressed MSU crystals-induced caspase-1 activation and IL-1β production in the air pouch exudates and the foot tissues, correlating with attenuation of inflammatory symptoms. CAPE directly associated with ASC as shown by SPR analysis and co-precipitation, resulting in blockade of NLRP3-ASC interaction induced by MSU crystals. Our findings provide a novel regulatory mechanism by which small molecules harness the activation of NLRP3 inflammasome by presenting ASC as a new target. Furthermore, the results suggest the preventive or therapeutic strategy for NLRP3-related inflammatory diseases such as gouty arthritis using orally available small molecules.
authors.affiliation: BK21plus team, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Lee
authors.affiliation: BK21plus team, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
authors.forename: Gabsik
authors.initials: G
authors.lastname: Yang
authors.affiliation: Daegu-Gyeongbuk Medical Innovation Foundation, New Drug Development Center, Daegu, 41061 Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Seongkeun
authors.initials: S
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
authors.affiliation: School of Chemistry and biochemistry and Graduate school of Biochemistry, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: School of Chemistry and biochemistry and Graduate school of Biochemistry, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Park
authors.affiliation: BK21plus team, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006073:Gout / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D050866:Liquid Crystals / Q000009:adverse effects / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D014527:Uric Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins; D002109:Caffeic Acids; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C498534:Pycard protein, mouse; D014527:Uric Acid; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol