Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout

DANG Wan-tai; XU Dan; ZHOU Jing-guo

doi:10.1007/s11655-022-3720-7

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Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout

Original Article | Updated：2023-01-05

- Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout
- Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout
- 中国结合医学杂志（英文版） 2023年29卷第1期页码：10-18
- Affiliations：
  
  Chengdu Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu (610500), China
- Author bio：
  
  Prof. XU Dan, E-mail: 447926416@qq.com
- Funds：
  
  the Innovative Team Building Project of Chengdu Medical College(CYTD18-03);the Key Projects of the First Affiliated Hospital of Chengdu Medical College(CYFY2019ZD01);Project of Sichuan Provincial Administration of Traditional Chinese Medicine(2020JC0023)
- DOI：10.1007/s11655-022-3720-7
  中图分类号：
- 纸质出版日期：2023-01-01，
  
  网络出版日期：2022-09-20，
  
  录用日期：2021-09-15
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Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout[J]. 中国结合医学杂志（英文版）, 2023,29(1):10-18.

DANG Wan-tai, XU Dan, ZHOU Jing-guo. Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout[J]. Chinese Journal of Integrative Medicine, 2023,29(1):10-18.
Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout[J]. 中国结合医学杂志（英文版）, 2023,29(1):10-18. DOI： 10.1007/s11655-022-3720-7.

DANG Wan-tai, XU Dan, ZHOU Jing-guo. Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout[J]. Chinese Journal of Integrative Medicine, 2023,29(1):10-18. DOI： 10.1007/s11655-022-3720-7.

摘要

Abstract

Objective:

To determine the effects of berberine (BBR) on the activation of toll-like receptor 4 (TLR4)

nuclear factor (NF) κB (NF-κB) signaling and NLRP3 inflammasome in patients with gout.

Methods:

Peripheral blood mononuclear cells (PBMCs) were obtained from 24 acute (AP) and 41 non-acute (NAP) phases of primary gout patients

respectively

as well as 30 healthy controls (HC). TLR4

NF-κB (p65)

NLRP3

apoptosis-associated specklike protein containing a CARD (PYCARD)

cysteinyl aspartate specific proteinase-1 (CASP1)

and interleukin-1β (IL-1β) mRNA expression levels in PBMCs were measured by quantitative reverse transcriptase polymerase chain reaction. The protein levels of TLR4

myeloid differentiation factor 88 (MyD88)

NF-κB (p50/65)

inhibitor of kappa B kinase α/β (IKKα/β)

NF-κB inhibitor α (IKBα)

phospho-IKKα/β (p-IKKα/β)

NLRP3

PYCARD

and CASP1 were monitored by Western blotting. Serum IL-1β protein level was measured using enzyme-linked immunosorbent assay (ELISA). In addition

PBMCs from HC and macrophages derived from a spontaneously immortalized monocyte-like cell line (THP-1) were stimulated using monosodium urate (MSU

100 μg/mL)

0.1% dimethyl sulfoxide

25 μmol/L BBR

and 10

and 50 μmol/L BBR+100 μg/mL MSU for different time periods. The protein levels of IL-1β and IL-18 in cell culture supernatants was measured by ELISA

and the protein expressions of TLR4

MyD88

NF-κB (p50/p65)

IKKα/β

IκBα

p-IKKα/β

NLRP3

PYCARD

and CASP1 in macrophages were analyzed by Western blotting.

Results:

(1) TLR4

NF-κB (p65)

PYCARD

CASP1

and IL-1β mRNA levels in PBMCs were significantly higher in the AP group than in the HC group (

0.05). The NLRP3 mRNA expression levels in PBMCs were found to be significantly lower in the AP and NAP groups than in the HC group (

0.05

0.01). (2) The protein levels of TLR4

IKKβ

MyD88

NF-κB

p-IKKα/β

PYCARD

and CASP1 in PBMCs were significantly higher

and those of IκBα

IKKα

and NLRP3 were found to be significantly lower in the AP group than in the HC group (

0.05 or

0.01). (3) The serum IL-1β protein levels were significantly higher in the AP and NAP groups than in the HC group (

0.01). (4) The IL-1β protein level was significantly lower in the culture supernatants of the PBMCs stimulated with MSU for 3 and 6 h in the 25 and 50 μmoL/L BBR groups compared with that in the MSU group (

0.01). (5) The protein levels of IL-1β and IL-18 were also significantly lower in the culture supernatants of macrophages stimulated with MSU for 3 and 6 h in BBR groups compared with those in the MSU group (

0.01). (6) The protein levels of TLR4

MyD88

NF-κB (p50

p65

p105)

IKKα/β

p-IκBα

p-IKKα/β

PYCARD

and CASP1 were significantly differed between the macrophages stimulated with MSU for 0.5 and 6 h in BBR groups compared with those in the MSU group (

0.05 or

0.01).

Conclusions:

Activation of TLR4-NFκB signaling and NLRP3 inflammasome by MSU crystals drives the progression of gout inflammation. BBR ameliorates gouty inflammation

which is mechanistically associated with its regulation of TLR4-NF-κB signaling and NLRP3 inflammasome expression.

关键词

Keywords

berberinegoutTLR4-NF-κBNLRP3 inflammasomemonosodium urate

references

Richette P, Bardin T. Gout. Lancet 2010;375:318-328.

van Durme CM, Spaetgens B, Boonen A, de Vries F.Risk of vascular disease with gout: overadjustment of the statistical analyses? Ann Rheum Dis 2015;74:e9.

Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 2015;21:248-255.

Zhang Y, Lu Y, Ma L, Cao X, Xiao J, Chen J, et al.Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NFκB signaling and protects against endotoxin shock. Immunity 2014;40:501-514.

Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, et al.Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 2015;160:62-73.

Cai X, Chen J, Xu H, Liu S, Jiang QX, Halfmann R, et al.Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation.Cell 2014;156:1207-1222.

Dalbeth N, Choi HK, Joosten LAB, Khanna PP, Matsuo H,Perez-Ruiz F, et al. Gout. Nat Rev Dis Primers 2019;5:69.

Talty A, Deegan S, Ljujic M, Mnich K, Naicker SD, Quandt D,et al. Inhibition of IRE1α RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1β. Cell Death Dis 2019;10:622.

Xian X, Sun B, Ye X, Zhang G, Hou P, Gao H. Identification and analysis of alkaloids in cortex Phellodendron amurense by high-performance liquid chromatography with electrospray ionization mass spectrometry coupled with photodiode array detection. J Sep Sci 2014;37:1533-1545.

Chen CC, Hung TH, Lee CY, Wang LF, Wu CH, Ke CH,et al. Berberine protects against neuronal damage via suppression of glia-mediated inflammation in traumatic brain injury. PLoS One 2014;9:e115694.

Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR,Berendsen D, et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2015;74:1789-1798.

Huang Z, Ye B, Han J, Kong F, Shan P, Lu Z, et al. NACHT,LRR and PYD domains-containing protein 3 inflammasome is activated and inhibited by berberine via toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB pathway, in phorbol 12-myristate 13-acetate-induced macrophages. Mol Med Rep 2018;17:2673-2680.

Mylona EE, Mouktaroudi M, Crisan TO, Makri S, Pistiki A,Georgitsi M, et al. Enhanced interleukin-1β production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res Ther 2012;14:R158.

Rossato MF, Hoffmeister C, Trevisan G, Bezerra F, Cunha TM, Ferreira J, et al. Monosodium urate crystal interleukin-1β release is dependent on Toll-like receptor 4 and transient receptor potential V1 activation. Rheumatology (Oxford)2020;59:233-242.

So AK, Martinon F. Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol 2017;13:639-647.

Mian Wu, Zhang M, Ma Y, Liu F, Chen S, Lu J, et al.Chaetocin attenuates gout in mice through inhibiting HIF-1α and NLRP3 inflammasome-dependent IL-1β secretion in macrophages. Arch Biochem Biophys 2019;670:94-103.

Vande Walle L, van Opdenbosch N, Jacques P, Fossoul A,Verheugen E, Vogel P, et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.Nature 2014;512:69-73.

Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases.Clin Exp Rheumatol 2016;34:12-16.

Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet 2016;388:2039-2052.

Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ,Wang C, et al. β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep 2017;18:2077-2087.

Renaudin F, Orliaguet L, Castelli F, Fenaille F, Prignon A,Alzaid F, et al. Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages. Ann Rheum Dis 2020;79:1506-1514.

Jing N, Li X. Dihydromyricetin attenuates inflammation through TLR4/NF-kappaB pathway. Open Med (Wars)2019;14:719-725.

Chen B, Li H, Ou G, Ren L, Yang X, Zeng M. Curcumin attenuates MSU crystal-induced inflammation by inhibiting the degradation of IκBα and blocking mitochondrial damage. Arthritis Res Ther 2019;21:193.

Dang W, Xu D, Xie W, Zhou J. Study on the expressions of NLRP3 gene transcript variants in peripheral blood monocytes of primary gout patients. Clin Rheumatol 2018;37:2547-2555.

Wang K, Chai L, Feng X, Liu Z, Liu H, Ding L, et al.Metabolites identification of berberine in rats using ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal 2017;139:73-86.

Lei X, Shan G, Zhang F, Liu P, Meng L, Jia T. Determination and comparison of alkaloids and triterpenes among tissues after oral administration of crude and processed Phellodendri Chinensis Cortex by UPLC-QqQ-MS. Nat Prod Res 2020;34:1337-1340.

Cicero AF, Baggioni A. Berberine and its role in chronic disease. Adv Exp Med Biol 2016;928:27-45.

Ma X, Chen Z, Wang L, Wang G, Wang Z, Dong X,et al. The pathogenesis of diabetes mellitus by oxidative stress and inflammation: its inhibition by berberine. Front Pharmacol 2018;9:782.

Zhang W, Xu JH, Yu T, Chen QK. Effects of berberine and metformin on intestinal inflammation and gut microbiome composition in db/db mice. Biomed Pharmacother 2019;118:109131.

Wang Z, Chen Z, Chen T, Yi T, Zheng Z, Fan H, et al.Berberine attenuates inflammation associated with delayed-type hypersensitivity via suppressing Th1 response and inhibiting apoptosis. Inflammation 2017;40:221-231.

Xu X, Yi H, Wu J, Kuang T, Zhang J, Li Q, et al.Therapeutic effect of berberine on metabolic diseases:both pharmacological data and clinical evidence. Biomed Pharmacother 2021;133:110984.

Wu J, Luo Y, Jiang Q, Li S, Huang W, Xiang L, et al. Coptisine from Coptis chinensis blocks NLRP3 inflammasome activation by inhibiting caspase-1. Pharmacol Res 2019;147:104348.

Gao MY, Chen L, Yang L, Yu X, Kou JP, Yu BY. Berberine inhibits LPS-induced TF procoagulant activity and expression through NF-κB/p65, Akt and MAPK pathway in THP-1 cells. Pharmacol Rep 2014;66:480-484.

Liu H, Yan Z, Zhao Y, Ma X, Zhang H, Wang X, et al. A peptide derived from IKK-interacting protein attenuates NF-κB activation and inflammation. J Immunol 2021;207:1652-1661.

Veluthakal R, Oh E, Ahn M, Chatterjee Bhowmick D,Thurmond DC. Syntaxin 4 mediates NF-κB signaling and chemokine ligand expression via specific interaction with IκBβ. Diabetes 2021;70:889-902.

Jimi E, Fei H, Nakatomi C. NF-κB signaling regulates physiological and pathological chondrogenesis. Int J Mol Sci 2019;20:6275.

Zhou Y, Ming J, Deng M, Li Y, Li B, Li J, et al. Berberine-mediated up-regulation of surfactant protein D facilitates cartilage repair by modulating immune responses via the inhibition of TLR4/NF-κB signaling. Pharmacol Res 2020;155:104690.

Yao M, Fan X, Yuan B, Takagi N, Liu S, Han X, et al.Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell. BMC Complement Altern Med 2019;19:216.

Liu H, You L, Wu J, Zhao M, Guo R, Zhang H, et al.Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS. J Leukoc Biol 2020;108:253-266.

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