Effectiveness of Huai Qi Huang Granules on Juvenile Collagen-induced Arthritis and Its Influence on Pyroptosis Pathway in Synovial Tissue

Abstract

Huai Qi Huang (HQH) exerts great effects in clinic, such as anti-inflammation, immune-regulation, anti-cancer, and so on. However, the mechanism by which HQH protects juvenile idiopathic arthritis (JIA) is obscure. Thus, we explored deeply the protective mechanisms in juvenile collagen-induced arthritis (CIA) rat model. Pyroptosis is Gasdermin D (GSDMD)-dependent programmed cell death, involved in many diseases, such as sepsis. We investigated whether GSDMD-induced pyroptosis take part in mechanisms of juvenile CIA arthritis. Juvenile Wistar rats (3-4 weeks) were injected intradermally with fully emulsified bovine type II collagen and complete Freund’s adjuvant to establish CIA rat models. Later, the CIA rats received oral administration of HQH (4.16 g/kg) once a day from the day 21 of modeling, with the treatment lasting for 28 days. Varieties of indicators were measured for evaluation of anti-inflammation effect of HQH, including hind paw swelling, arthritis scores, micro CT, and histopathological changes and the level of pro-inflammatory cytokines in the serum, including tumor necrosis factor alpha (TNF-±) and interleukin-18 (IL-18). The expression of GSDMD and caspase-1 in the joint synovial tissues was detected. The results demonstrated that the expression of the pyroptotic protein GSDMD and its upstream caspase-1 was significantly increased in the synovial tissues of CIA rats. The treatment of HQH ameliorated the symptoms in CIA rats, reduced levels of pro-inflammatory cytokines and hind paw swelling, down-regulated the expression of GDSMD and caspase-1. GSDMD-induced pyroptosis participated in the pathogenesis of CIA rats. The study supported that HQH can effectively improve joints inflammation of juvenile collagen-induced arthritis rats by inhibiting pyroptosis pathway in the joint synovial tissues.

Keywords

Huai Qi Huang / juvenile collagen-induced arthritis / Gasdermin D / pyroptosis

References

[1] FellasA, HawkeF, SantosD, et al.. Prevalence, presentation and treatment of lower limb pathologies in juvenile idiopathic arthritis: A narrative review. J Paediatr Child Health, 2017, 53(9): 836-840

[2] CimazR. Systemic-onset juvenile idiopathic arthritis. Autoimmun Rev, 2016, 15(9): 931-934

[3] NigrovicPA. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. Proc Natl Acad Sci USA, 2015, 112(52): 15 785-15 786

[4] AksentijevichI, McdermottMF. Lessons from characterization and treatment of the autoinflammatory syndromes. Curr Opin Rheumatol, 2017, 29(2): 187-194

[5] CushJ J. Autoinflammatory syndromes. Dermatol Clin, 2013, 31(3): 471

[6] PepperRJ, LachmannHJ. Autoinflammatory syndromes in children. Indian J Pediatr, 2016, 83(3): 242-247

[7] YangC, ChiangB. Inflammasomes and human autoimmunity: A comprehensive review. J Autoimmun, 2015, 61: 1-8

[8] LamkanfiM, DixitVM. Mechanisms and functions of inflammasomes. Cell, 2014, 157(5): 1013-1022

[9] ShiJ, ZhaoY, WangK, et al.. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526(7575): 660-665

[10] DingJ, WangK, LiuW, et al.. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature, 2016, 535(7610): 111

[11] YangJ, LiuZ, WangC, et al.. Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor. Proc Natl Acad Sci USA, 2018, 115(26): 6792-6797

[12] LiuX, ZhangZ, RuanJ, et al.. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature, 2016, 535(7610): 153

[13] ShiJ, GaoW, ShaoF. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem Sci, 2017, 42(4): 245-254

[14] LiuZ, WangC, RathkeyJK, et al.. Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition. Structure, 2018, 26(5): 778

[15] HeWT, WanH, HuL, et al.. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res, 2015, 25(12): 1285-1298

[16] Gao Y, Zhai J, Chai Y. Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis. Mediat Inflamm, 2018(5823823)

[17] KannegantiA, MalireddiRKS, SaavedraPHV, et al.. GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever. J Exp Med, 2018, 215(6): 1519-1529

[18] WangWJ, ChenD, JiangMZ, et al.. Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle-related proteins. J Digest Dis, 2018, 19(2): 74-83

[19] MckenzieBA, MamikMK, SaitoLB, et al.. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc Natl Acad Sci USA, 2018, 115(26): E6065-E6074

[20] MitraS, ExlineM, HabyarimanaF, et al.. Microparticulate Caspase 1 Regulates Gasdermin D and Pulmonary Vascular Endothelial Cell Injury. Am J Resp Cell Mol, 2018, 59(1): 56-64

[21] XuB, JiangM, ChuY, et al.. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J Hepatol, 2018, 68(4): 773-782

[22] HanJ, LinM, ZhouD, et al.. Huang Qi Huai Granules Induce Apoptosis in Acute Lymphoblastic Leukemia Cells through the Akt/FoxO1 Pathway. Cell Physiol Biochem, 2016, 38(5): 1803-1814

[23] SongX, LiY, ZhangH, et al.. The anticancer effect of Huaier. Oncol Rep, 2015, 34(1): 12-21

[24] ZhangS, CuiL. Research progress of huaier and its compound preparation Huai Qi Huang granules. Yixue Zongshu (Chinese), 2015, 21(1): 114-116

[25] MoudgilKD, BermanBM. Traditional Chinese medicine: potential for clinical treatment of rheumatoid arthritis. Expert Rev Clin Immu, 2014, 10(7): 819-822

[26] ShanJ, PengL, QianW, et al.. Integrated Serum and Fecal Metabolomics Study of Collagen-Induced Arthritis Rats and the Therapeutic Effects of the Zushima Tablet. Front Pharmacol, 2018, 9: 891

[27] HsuY, HsiehP, ChangM. Interleukin-19 blockade attenuates collagen-induced arthritis in rats. Rheumatology, 2012, 51(3): 434-442

[28] AnsariMM, Neha, KhanHA. Effect of cadmium chloride exposure during the induction of collagen induced arthritis. Chem Biol Interact, 2015, 238: 55-65

[29] ShimizuM, NakagishiY, InoueN, et al.. Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Clin Immunol, 2015, 160(2): 277-281

[30] ShimizuM, NakagishiY, KasaiK, et al.. Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine, 2012, 58(2): 287-294

[31] de JagerW, VastertSJ, BeekmanJM, et al.. Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis Rheumatol, 2009, 60(9): 2782-2793

[32] ShimizuM, NakagishiY, KasaiK, et al.. Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine, 2012, 58(2): 287-294

[33] ScardapaneA, FerranteR, NozziM, et al.. TNF-α gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response. Semin Arthritis Rheu, 2015, 45(1): 35-41

[34] Kaminiarczyk-PyzalkaD, AdamczakK, MikosH, et al.. Proinflammatory cytokines in monitoring the course of disease and effectiveness of treatment with etanercept (ETN) of children with oligo- and polyarticular juvenile idiopathic arthritis (JIA). Clin Lab, 2014, 60(9): 1481-1490

[35] TakaharaT, ShimizuM, NakagishiY, et al.. Serum IL-18 as a potential specific marker for differentiating systemic juvenile idiopathic arthritis from incomplete Kawasaki disease. Rheumatol Int, 2015, 35(1): 81-84

[36] ShiJ, GaoW, ShaoF. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem Sci, 2017, 42(4): 245-254

[37] RussoHM, RathkeyJ, Boyd-TresslerA, et al.. Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides. J Immunol, 2016, 197(4): 1353-1367

[38] VanajaSK, RathinamVAK, FitzgeraldKA. Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol, 2015, 25(5): 308-315

[39] MatmatiM, JacquesP, MaelfaitJ, et al.. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet, 2011, 43(9): 129-908

[40] Vande WalleL, Van OpdenboschN, JacquesP, et al.. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature, 2014, 512(7512): 69

[41] MathewsRJ, RobinsonJI, BattellinoM, et al.. Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3 -inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis, 2014, 73(6): 1202-1210

[42] JenkoB, PraprotnikS, TomsicM, et al.. NLRP3 and CARD8 Polymorphisms Influence Higher Disease Activity in Rheumatoid Arthritis. J Med Biochem, 2016, 35(3): 319-323

[43] SunY, SunT, WangF, et al.. A polysaccharide from the fungi of Huaier exhibits anti-tumor potential and immunomodulatory effects. Carbohyd Polym, 2013, 92(1): 577-582

[44] WuT, ChenW, LiuS, et al.. Huaier suppresses proliferation and induces apoptosis in human pulmonary cancer cells via upregulation of miR-26b-5p. Febs Lett, 2014, 588(12): 2107-2114

[45] LiC, WuX, ZhangH, et al.. A Huaier polysaccharide inhibits hepatocellular carcinoma growth and metastasis. Tumor Biol, 2015, 36(3): 1739-1745

[46] XieH, XuZ, TangJ, et al.. Effect of Huaier on the proliferation and apoptosis of human gastric cancer cells through modulation of the PI3K/AKT signaling pathway. Exp Ther Med, 2015, 10(3): 1212-1218

[47] LiT, MaoJ, HuangL, et al.. Huaiqihuang may protect from proteinuria by resisting MPC5 podocyte damage via targeting p-ERK/CHOP pathway. Bosnian J Basic Med, 2016, 16(3): 193-200

[48] SunW, ZhuZ, YuJ, et al.. Effects of Chinese herbal medicine Huaiqihuang Granule on nephrin and podocin expressions in renal tissues of rats with adriamycin-induced nephrosis. Zhong Xi Yi Jie He Xue Bao (Chinese), 2011, 9(5): 546-552

[49] ZhuC, HuangS, DingG, et al.. Protective effects of Huang Qi Huai granules on adriamycin nephrosis in rats. Pediatr Nephrol, 2011, 26(6): 905-913

[50] MaY, JiangJ, GaoY, et al.. Research progress of the relationship between pyroptosis and disease. Am J Transl Res, 2018, 10(7): 2213-2219