Neuroprotective effect of heat shock protein 60 on matrine‑suppressed microglial activation

Zhang,Rui; Li,Yunhong; Hou,Xiaolin; Miao,Zhenhua; Wang,Yin

doi:10.3892/etm.2017.4691

Neuroprotective effect of heat shock protein 60 on matrine‑suppressed microglial activation

Authors:
- Rui Zhang
- Yunhong Li
- Xiaolin Hou
- Zhenhua Miao
- Yin Wang
View Affiliations

Affiliations: Ningxia Key Laboratory of Cerebrocranial Diseases, Basic Medical School of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
Published online on: June 27, 2017 https://doi.org/10.3892/etm.2017.4691
Pages: 1832-1836

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Matrine (MT) is the primary active alkaloid separated from members of the Sophora genus. Previous studies have reported that MT has anti‑inflammatory effects in the central nervous system (CNS). However, the underlying molecular mechanism of the neuroprotective effect of MT remains unclear, particularly the role of heat shock protein 60 (HSP60). Microglia are macrophages in the CNS that serve an essential role in the innate immune system by producing various proinflammatory and neurotoxic factors. In addition, HSP60 is released by activated microglia causing an autoimmune response. The present study aimed to investigate whether MT could inhibit the activation of microglia via suppressing the HSP60 signaling pathway. The results demonstrated that the expression and release of HSP60 in LPS‑activated BV2 microglial cells was significantly decreased by MT treatment. Extracellular HSP60 is a ligand of toll like receptor 4 (TLR‑4); thus, it was hypothesized that secreted HSP60 could bind to TLR‑4 on microglia and activate the TLR‑4 signaling pathway. As expected, western blotting and ELISA results revealed that MT significantly inhibited the LPS‑induced increase in TLR‑4, myeloid differentiation primary response protein MyD88, caspase‑3 and tumor necrosis factor‑α. In conclusion, the results of the present study provide a novel direction for the prevention and treatment of neurodegenerative diseases characterized by microglial activation.

View Figures

View References

1	Perry VH, Nicoll JA and Holmes C: Microglia in neurodegenerative disease. Nat Rev Neurol. 6:193–201. 2010. View Article : Google Scholar : PubMed/NCBI
2	Block ML, Zecca L and Hong JS: Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Rev Neurosci. 8:57–69. 2007. View Article : Google Scholar
3	Liu B and Hong JS: Role of microglia in inflammation-mediated neurodegenerative disease: Mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 304:1–7. 2003. View Article : Google Scholar : PubMed/NCBI
4	Hanisch Uk and Kettenmann H: Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 10:1387–1394. 2007. View Article : Google Scholar : PubMed/NCBI
5	Gehrmann J, Matsumoto Y and Kreutzberg GW: Microglia: Intrinsic immuneffector cell of the brain. Brain Res Rev. 20:269–287. 1995. View Article : Google Scholar : PubMed/NCBI
6	Lynch MA: The multifaceted profile of activated microglia. Mol Neurobiol. 40:139–156. 2009. View Article : Google Scholar : PubMed/NCBI
7	Li YH, Teng P, Wang Y, Zhang YM, Ma CJ and Pu J: Expression and regulation of HSP60 in activated microglia cells. J Ningxia Med Univ. 8:712–714. 2011.
8	Zhang D, Sun L, Zhu H, Wang L, Wu W, Xie J and Gu J: Microglial LOX-1 reacts with extracellular HSP60 to bridge neuroinflammation and neurotoxicity. Neurochem Int. 61:1021–1035. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cheng W, Li Y, Hou X, Zhang N, Ma J, Ding F, Li F, Miao Z, Zhang Y, Qi Q, et al: HSP60 is involved in the neuroprotective effects of naloxone. Mol Med Rep. 10:2172–2176. 2014.PubMed/NCBI
10	Zhao P, Zhou R, Zhu XY, Hao YJ, Li N, Wang J, Niu Y, Sun T, Li YX and Yu JQ: Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice. Int J Mol Med. 36:633–644. 2015.PubMed/NCBI
11	Rong B, Zhao C, Gao W and Yang S: Matrine promotes the efficacy and safety of platinum-based doublet chemotherapy for advanced non-small cell lung cancer. Int J Clin Exp Med. 8:14701–14717. 2015.PubMed/NCBI
12	Kan QC, Pan QX, Zhang XJ, Chu YJ, Liu N, Lv P, Zhang GX and Zhu L: Matrine ameliorates experimental autoimmune encephalomyelitis by modulating chemokines and their receptors. Exp Mol Pathol. 99:212–219. 2015. View Article : Google Scholar : PubMed/NCBI
13	Kan QC, Lv P, Zhang XJ, Xu YM, Zhang GX and Zhu L: Matrine protects neuro-axon from CNS inflammation-induced injury. Exp Mol Pathol. 98:124–130. 2015. View Article : Google Scholar : PubMed/NCBI
14	Zhang ML, Zhang XJ, Kang J, Zhang HJ, Chen XL, Liu N, Liu SQ, Ma WD, Zhang GX and Zhu L: Matrine promotes NT3 expression in CNS cells in experimental autoimmune encephalomyelitis. Neurosci Lett. 649:100–106. 2017. View Article : Google Scholar : PubMed/NCBI
15	Chandra D, Choy G and Tang DG: Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. J Biol Chem. 282:31289–31301. 2007. View Article : Google Scholar : PubMed/NCBI
16	Kreutzberg GW: Microglia: A sensor for pathological events in the CNS. Trends Neurosci. 19:312–328. 1996. View Article : Google Scholar : PubMed/NCBI
17	Teng P, Li Y, Cheng W, Zhou L, Shen Y and Wang Y: Neuroprotective effects Of Lycium barbarum polysaccharides in lipopolysaccharide-induced BV2 microglia cells. Mol Med Rep. 7:1977–1981. 2013.PubMed/NCBI
18	Miao RM, Fang ZH and Yao Y: Therapeutic efficacy of tetrandrine tablets combined with matrine injection in treatment of silicosis. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 30:778–780. 2012.(In Chinese). PubMed/NCBI
19	Lao Y: Clinical study of matrine injection on preventing liver function damage of anti-tumor drugs during chemotherapy of breast cancer. Zhong Yao Cai. 28:735–737. 2005.(In Chinese). PubMed/NCBI
20	Quintana FJ and Cohen IR: HSP60 speaks to the immune system in many voices. Novartis Found symp. 291:101–114. 2008. View Article : Google Scholar : PubMed/NCBI
21	Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G, Nitsch R and Werber JR: A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci. 28:2320–2331. 2008. View Article : Google Scholar : PubMed/NCBI
22	Hansen JJ, Bross P, Westergaard M, Nielsen MN, Eiberg H, Børglum AD, Mogensen J, Kristiansen K, Bolund L and Gregersen N: Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localised head to head on chromosome 2 separated by a bidirectional promoter. Hum Genet. 112:71–77. 2003. View Article : Google Scholar : PubMed/NCBI
23	Cao Z, Ma J and Yuan WJ: Heat shock protein 60 in cell apoptosis. Sheng Li Ke Xue Jin Zhan. 39:267–270. 2008.(In Chinese). PubMed/NCBI
24	Gupta S and Knowlton AA: HSP60 trafficking in adult cardiac myocytes: Role of the exosomal pathway. Am J Physiol Heart Circ Physiol. 292:H3052–H3056. 2007. View Article : Google Scholar : PubMed/NCBI
25	Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL and Joseph B: Caspase signalling controls microglia activation and neurotoxicity. Nature. 472:319–324. 2011. View Article : Google Scholar : PubMed/NCBI
26	Samali A, Cai J, Zhivotovsky B, Jones DP and Orrenius S: Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J. 18:2040–2048. 1999. View Article : Google Scholar : PubMed/NCBI
27	Wang Y, Chen L, Hagiwara N and Knowlton AA: Regulation of heat shock protein 60 and 72 expression in the failing heart. J Mol Cell Cardiol. 48:360–366. 2010. View Article : Google Scholar : PubMed/NCBI
28	Rosenberger K, Dembny P, Derkow K, Engel O, Krüger C, Wolf SA, Kettenmann H, Schott E, Meisel A and Lehnardt S: Intrathecal heat shock protein 60 mediates neurodegeneration and demyelination in the CNS through a TLR-4 and MyD88-dependent pathway. Mol Neurodegener. 10:52015. View Article : Google Scholar : PubMed/NCBI
29	Montgomery SL and Bowers WJ: Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 7:42–59. 2012. View Article : Google Scholar : PubMed/NCBI