Abstract
Gout, the most prevalent inflammatory arthritis worldwide, released interleukin-1β (IL-1β) and Cathepsin B inflammatory mediators that constitute the hallmark of the disease. Herein we aimed to investigate whether procyanidin B2 (PCB2), a natural dietary compound, can suppress MSU crystals-stimulated gouty inflammation. Treated with lipopolysaccharide (LPS) plus MSU, both mouse peritoneal macrophages (MPM) and mouse bone marrow-derived macrophages (BMDM) released a large amount of mature IL-1β compared to those treated with MSU or LPS alone, while IL-1β release was blocked by TLR4 and its downstream effector inhibitors. In two mouse models of gout, oral administration of PCB2 suppressed MSU crystals-induced increasing expression of IL-1β, Cathepsin B and NLRP3 in the air pouch skin and paws, accompanied with the downregulation prostaglandin E2 (PGE2) in pouch exudates. Inflammatory immune cell infiltration including macrophages and neutrophils were significantly blocked by PCB2 in air pouch skin and paws of mice gout groups. PCB2 also suppressed the release of IL-1β and Cathepsin B induced by MSU plus LPS in MPM. Our results suggest that the inhibitory effects of PCB2 on NLRP3 inflammasome may alleviate inflammatory response in gout, and this might be a promising anti-inflammatory mechanism of PCB2 against the inflammation in gout.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- AMPK:
-
AMP-activated protein kinase
- DMEM:
-
Dulbecco's modified Eagle medium
- IL-1β:
-
Interleukin-1β
- IL-1Ra:
-
Interleukin-1 receptor antagonist
- IL-36Ra:
-
Interleukin-36 receptor antagonist
- MSU crystals:
-
Monosodium uric acid crystals
- NLRP3:
-
Nod-like receptor (NLR)-family protein 3
- PCB2:
-
Procyanidin B2
- LPS:
-
Lipopolysaccharide
- P2X7R:
-
Purinergic 2X7 receptor
- TLR4:
-
Toll-like receptor 4
- NF-κB:
-
Nuclear factor-kappa B
- BMDMs:
-
Bone marrow-derived macrophages
- MPM:
-
Mouse peritoneal macrophages
- PGE2:
-
Prostaglandin E2
References
Abais JM, Xia M, Zhang Y, Boini KM, Li PL (2015) Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal 22:1111–1129. https://doi.org/10.1089/ars.2014.5994
Amaral EP et al (2018) Lysosomal cathepsin release is required for NLRP3-inflammasome activation by Mycobacterium tuberculosis in infected macrophages. Front Immunol 9:1427
Bai H, Yang B, Yu W, Xiao Y, Yu D, Zhang Q (2018) Cathepsin B links oxidative stress to the activation of NLRP3 inflammasome. Exp Cell Res 362:180–187. https://doi.org/10.1016/j.yexcr.2017.11.015
Chevriaux A et al (2020) Cathepsin B is required for NLRP3 inflammasome activation in macrophages, through NLRP3 interaction. Front Cell Dev Biol 8:167. https://doi.org/10.3389/fcell.2020.00167
Chuang J-P, Kao C-Y, Lee J-C, Ling P, Maa M-C, Leu T-H (2020) EPS8 regulates an NLRP3 inflammasome-independent caspase-1 activation pathway in monosodium urate crystal-treated RAW264.7 macrophages. Biochem Biophys Res Commun 530:487–493. https://doi.org/10.1016/j.bbrc.2020.05.084
Dalbeth N, Lauterio TJ, Wolfe HR (2014) Mechanism of action of colchicine in the treatment of gout. Clin Ther 36:1465–1479. https://doi.org/10.1016/j.clinthera.2014.07.017
Fink SL, Bergsbaken T, Cookson BT (2008) Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci USA 105:4312–4317. https://doi.org/10.1073/pnas.0707370105
Funck-Brentano T, Salliot C, Leboime A, Zafrani L, Servais A, Larousserie F, Dougados M (2011) First observation of the efficacy of IL-1ra to treat tophaceous gout of the lumbar spine. Rheumatology (Oxford) 50:622–624. https://doi.org/10.1093/rheumatology/keq358
Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39:1003–1018. https://doi.org/10.1016/j.immuni.2013.11.010
Gicquel T et al (2015) IL-1β production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J 29:4162–4173. https://doi.org/10.1096/fj.14-267393
Goldberg EL et al (2017) beta-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep 18:2077–2087. https://doi.org/10.1016/j.celrep.2017.02.004
Guo X, Chen Y, Li Q, Yang X, Zhao G, Peng Y, Zheng J (2019) Studies on hepatotoxicity and toxicokinetics of colchicine. J Biochem Mol Toxicol 33:e22366. https://doi.org/10.1002/jbt.22366
Hahn M, Frey S, Hueber AJ (2017) The novel interleukin-1 cytokine family members in inflammatory diseases. Curr Opin Rheumatol 29:208–213. https://doi.org/10.1097/BOR.0000000000000361
Hall CJ et al (2018) Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation. J Clin Investig 128:1752–1771. https://doi.org/10.1172/JCI94584
Khameneh HJ et al (2017) C5a regulates IL-1beta production and leukocyte recruitment in a murine model of monosodium urate crystal-induced peritonitis. Front Pharmacol 8:10. https://doi.org/10.3389/fphar.2017.00010
Lee HE et al (2016) Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout. Sci Rep 6:38622. https://doi.org/10.1038/srep38622
Lee HE, Yang G, Park YB, Kang HC, Cho YY, Lee HS, Lee JY (2019) Epigallocatechin-3-Gallate prevents acute gout by suppressing NLRP3 inflammasome activation and mitochondrial DNA synthesis. Molecules. https://doi.org/10.3390/molecules24112138
Li S et al (2013) Cathepsin B contributes to autophagy-related 7 (Atg7)-induced nod-like receptor 3 (NLRP3)-dependent proinflammatory response and aggravates lipotoxicity in rat insulinoma cell line. J Biol Chem 288:30094–30104. https://doi.org/10.1074/jbc.M113.494286
Li X et al (2018) Liver kinase B1/AMP-activated protein kinase-mediated regulation by gentiopicroside ameliorates P2X7 receptor-dependent alcoholic hepatosteatosis. Br J Pharmacol 175:1451–1470. https://doi.org/10.1111/bph.14145
Liu HJ et al (2017) Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression. J Neuroinflamm. 14:74. https://doi.org/10.1186/s12974-017-0849-y
Liu Q, Zhang D, Hu D, Zhou X, Zhou Y (2018) The role of mitochondria in NLRP3 inflammasome activation. Mol Immunol 103:115–124. https://doi.org/10.1016/j.molimm.2018.09.010
Liu Y et al (2019) Frontline science: reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis. J Leukoc Biol 105:11–24. https://doi.org/10.1002/JLB.3HI0518-193R
Marchetti C et al (2018) NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis. Arthritis Res Ther 20:169. https://doi.org/10.1186/s13075-018-1664-2
Martinez-Micaelo N, Gonzalez-Abuin N, Pinent M, Ardevol A, Blay M (2015) Procyanidin B2 inhibits inflammasome-mediated IL-1beta production in lipopolysaccharide-stimulated macrophages. Mol Nutr Food Res 59:262–269. https://doi.org/10.1002/mnfr.201400370
Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S (2013) Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14:454–460. https://doi.org/10.1038/ni.2550
Pascual E, Addadi L, Andres M, Sivera F (2015) Mechanisms of crystal formation in gout-a structural approach. Nat Rev Rheumatol 11:725–730. https://doi.org/10.1038/nrrheum.2015.125
Pellegrini C, Antonioli L, Lopez-Castejon G, Blandizzi C, Fornai M (2017) Canonical and non-canonical activation of NLRP3 inflammasome at the crossroad between immune tolerance and intestinal inflammation. Front Immunol 8:36. https://doi.org/10.3389/fimmu.2017.00036
Qing YF, Zhang QB, Zhou JG, Jiang L (2014) Changes in toll-like receptor (TLR)4-NFkappaB-IL1beta signaling in male gout patients might be involved in the pathogenesis of primary gouty arthritis. Rheumatol Int 34:213–220. https://doi.org/10.1007/s00296-013-2856-3
Rock KL, Kataoka H, Lai JJ (2013) Uric acid as a danger signal in gout and its comorbidities Nature reviews. Rheumatology 9:13–23. https://doi.org/10.1038/nrrheum.2012.143
Sakano K, Mizutani M, Murata M, Oikawa S, Hiraku Y, Kawanishi S (2005) Procyanidin B2 has anti- and pro-oxidant effects on metal-mediated DNA damage. Free Radic Biol Med 39:1041–1049. https://doi.org/10.1016/j.freeradbiomed.2005.05.024
Shi Y, Mucsi AD, Ng G (2020) Yan Shi.pdf
So AK, Martinon F (2017) Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol 13:639–647. https://doi.org/10.1038/nrrheum.2017.155
Su H, Li Y, Hu D, Xie L, Ke H, Zheng X, Chen W (2018) Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state. Free Radic Biol Med 126:269–286. https://doi.org/10.1016/j.freeradbiomed.2018.08.024
Suda M et al (2013) Syntheses of procyanidin B2 and B3 gallate derivatives using equimolar condensation mediated by Yb(OTf)3 and their antitumor activities. Bioorg Med Chem Lett 23:4935–4939. https://doi.org/10.1016/j.bmcl.2013.06.061
van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D (2014) Colchicine for acute gout. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD006190.pub2
Wu ZC, Xue Q, Zhao ZL, Zhou PJ, Zhou Q, Zhang Z, Deng JP, Yang K, Fan K, Fan H, Wang YF, Wang ZP (2019) Suppressive effect of Huzhentongfeng on experimental gouty arthritis: an in vivo and in vitro study. Evid Based Complement Altern Med 2019:1–15. https://doi.org/10.1155/2019/2969364
Yang H, Xiao L, Yuan Y, Luo X, Jiang M, Ni J, Wang N (2014) Procyanidin B2 inhibits NLRP3 inflammasome activation in human vascular endothelial cells. Biochem Pharmacol 92:599–606. https://doi.org/10.1016/j.bcp.2014.10.001
Zhang Q, Duan J, Yang B, Yu D, Liu L, Bai H (2018) Cathepsin B regulates the activation of NLRP3 inflammasome by calcium signaling. Neuropsychiatry 8:1899–1912. https://doi.org/10.4172/Neuropsychiatry.1000533
Zurek M (2006) Pathogenesis, diagnostics and therapy of gout. Vnitr Lek 52:736–741
Acknowledgements
This study was supported by a grant from the National Natural Science Foundation of China (81960677 and 81660689), and partially by Science and Technology Planning Projects from the Science and Technology Department of Jilin Province (20180414048GH, 20180201065YY and 20180519010JH) and Science and Technology Planning Project of the Jilin Provincial Education Department (JJKH20191155KJ).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have declared no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Qiao, CY., Li, Y., Shang, Y. et al. Management of Gout-associated MSU crystals-induced NLRP3 inflammasome activation by procyanidin B2: targeting IL-1β and Cathepsin B in macrophages. Inflammopharmacol 28, 1481–1493 (2020). https://doi.org/10.1007/s10787-020-00758-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-020-00758-8