Immune thrombocytopenia induces autophagy and suppresses apoptosis in megakaryocytes

Liu,Zhanshu; Mei,Tonghua

doi:10.3892/mmr.2018.9373

Immune thrombocytopenia induces autophagy and suppresses apoptosis in megakaryocytes

Authors:
- Zhanshu Liu
- Tonghua Mei
View Affiliations

Affiliations: Department of Hematology, Yongchuan Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: August 9, 2018 https://doi.org/10.3892/mmr.2018.9373
Pages: 4016-4022

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

Immune thrombocytopenia (ITP) is the main pathogenesis of excessive platelet destruction and abnormal megakaryocyte apoptosis, however, the mechanism underlying this abnormality in megakaryocytes remains to be elucidated. Since autophagy and apoptosis are closely interrelated, it can be speculated that the abnormal apoptosis of ITP megakaryocytes is associated with autophagy. To test this hypothesis, a total of 14 patients with ITP and 23 healthy controls were recruited. MEG‑01 cell line was cultured in vitro, and morphological changes were observed by light microscopy, apoptosis was evaluated by flow cytometric analysis of Annexin V‑FITC/propidium iodide staining and western blot analysis of B‑cell lymphoma (Bcl)‑2, Bcl‑associated X protein (Bax), Beclin‑1 and cleaved caspase 3. Apoptotic abnormalities and autophagy were observed in the ITP plasma group. Furthermore, Bax expression was downregulated, while Beclin‑1 was upregulated. Chloroquine can block autophagy induced by ITP and remove the ITP plasma inhibition of apoptosis. Therefore, it may be concluded that ITP may induce autophagy, the inhibition of which may be a novel treatment for ITP.

View Figures

View References

1	Li J, Van der Wal DE, Zhu G, Xu M, Yougbare I, Ma L, Vadasz B, Carrim N, Grozovsky R, Ruan M, et al: Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 6:77372015. View Article : Google Scholar : PubMed/NCBI
2	Zhou H, Hou Y, Liu X, Qiu J, Feng Q, Wang Y, Zhang X, Min Y, Shao L, Liu X, et al: Low-dose decitabine promotes megakaryocyte maturation and platelet production in healthy controls and immune thrombocytopenia. Thromb Haemost. 113:1021–1034. 2015. View Article : Google Scholar : PubMed/NCBI
3	Kashiwagi H and Tomiyama Y: Pathophysiology and management of primary immune thrombocytopenia. Int J Hematol. 98:24–33. 2013. View Article : Google Scholar : PubMed/NCBI
4	Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB and Tsujimoto Y: Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Boil. 6:1221–1228. 2004. View Article : Google Scholar
5	Houwerzijl EJ, Blom NR, Van der Want JJ, Esselink MT, Koornstra JJ, Smit JW, Louwes H, Vellenga E and de Wolf JT: Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 103:500–506. 2004. View Article : Google Scholar : PubMed/NCBI
6	Morishima N and Nakanishi K: Proplatelet formation in megakaryocytes is associated with endoplasmic reticulum stress. Genes Cells. 21:798–806. 2016. View Article : Google Scholar : PubMed/NCBI
7	Lee WS, Sung MS, Lee EG, Yoo HG, Cheon YH, Chae HJ and Yoo WH: A pathogenic role for ER stress-induced autophagy and er chaperone GRP78/BiP in T lymphocyte systemic lupus erythematosus. J Leukoc Biol. 97:425–433. 2015. View Article : Google Scholar : PubMed/NCBI
8	Yu L, Chen Y and Tooze SA: Autophagy pathway: Cellular and molecular mechanism. Autophagy. 14:207–215. 2018. View Article : Google Scholar : PubMed/NCBI
9	Liu Q, Luo XY, Jiang H, Yang MH, Yuan GH, Tang Z and Wang H: Hydroxychloroquine facilitates autophagosome formation but not degradation to suppress the proliferation of cervical cancer SiHa cells. Oncol Lett. 7:1057–1062. 2014. View Article : Google Scholar : PubMed/NCBI
10	Houwerzijl EJ, Blom NR, Van der Want JJ, Vellenga E and de Wolf JT: Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia. 20:1937–1942. 2006. View Article : Google Scholar : PubMed/NCBI
11	Xue E, Zhang Y, Song B, Xiao J and Shi Z: Effect of autophagy induced by dexamethasone on senescence in chondrocytes. Mol Med Rep. 14:3037–3044. 2016. View Article : Google Scholar : PubMed/NCBI
12	Yang L, Wang L, Zhao CH, Zhu XJ, Hou Y, Jun P and Hou M: Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia. Blood. 116:4307–4316. 2010. View Article : Google Scholar : PubMed/NCBI
13	Mariño G, Niso-Santano M, Baehrecke EH and Kroemer G: Self-consumption: The interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 15:81–94. 2014. View Article : Google Scholar : PubMed/NCBI
14	Zhou J, Zhou Y, Wen J, Sun X and Zhang X: Circulating myeloid-derived suppressor cells predict disease activity and treatment response in patients with immune thrombocytopenia. Braz J Med Biol Res. 50:e56372017. View Article : Google Scholar : PubMed/NCBI
15	Fabre C, Carvalho G, Tasdemir E, Braun T, Adès L, Grosjean J, Boehrer S, Métivier D, Souquère S, Pierron G, et al: NF-kappaB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene. 26:4071–4083. 2007. View Article : Google Scholar : PubMed/NCBI
16	De Botton S, Sabri S, Daugas E, Zermati Y, Guidotti JE, Hermine O, Kroemer G, Vainchenker W and Debili N: Platelet formation is the consequence of caspase activation within megakaryocytes. Blood. 100:1310–1317. 2002. View Article : Google Scholar : PubMed/NCBI
17	Kile BT: The role of apoptosis in megakaryocytes and platelets. Br J Haematol. 165:217–226. 2014. View Article : Google Scholar : PubMed/NCBI
18	Mukhopadhyay S, Panda PK, Sinha N, Das DN and Bhutia SK: Autophagy and apoptosis: Where do they meet? Apoptosis. 19:555–566. 2014. View Article : Google Scholar : PubMed/NCBI
19	Ruddy SC, Lau R, Cabrita MA, McGregor C, McKay BC, Murphy LC, Wright JS, Durst T and Pratt MA: Preferential estrogen receptor β ligands reduce Bcl-2 expression in hormone-resistant breast cancer cells to increase autophagy. Mol Cancer Ther. 13:1882–1893. 2014. View Article : Google Scholar : PubMed/NCBI
20	Song DD, Zhang TT, Chen JL, Xia YF, Qin ZH, Waeber C and Sheng R: Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain. Cell Death Dis. 8:e29122017. View Article : Google Scholar : PubMed/NCBI
21	Su M, Mei Y and Sinha S: Role of the crosstalk between autophagy and apoptosis in cancer. J Oncol. 2013:102710352013. View Article : Google Scholar
22	Li M, Gao P and Zhang J: Crosstalk between autophagy and apoptosis: Potential and emerging therapeutic targets for cardiac diseases. Int J Mol Sci. 17:3322016. View Article : Google Scholar : PubMed/NCBI
23	Zhong JT, Xu Y, Yi HW, Su J, Yu HM, Xiang XY, Li XN, Zhang ZC and Sun LK: The BH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin 1 interaction in human glioma U251 cells. Cancer Lett. 323:180–187. 2012. View Article : Google Scholar : PubMed/NCBI