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MiR-30a Positively Regulates the Inflammatory Response of Microglia in Experimental Autoimmune Encephalomyelitis

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Abstract

Multiple sclerosis (MS) is a classical inflammatory demyelinating disease of the central nervous system (CNS). Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS. In the present study, we found that miR-30a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis (EAE) at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30a promoted the apoptosis of oligodendrocyte precursor cells (OPCs), and inhibited OPC differentiation. In vivo, overexpressing miR-30a in transplanted microglia exacerbated the progression of EAE. Overexpression and knock-down experiments in primary cultured mouse microglia showed that miR-30a increased the expression of IL-1β and iNOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206. Mechanistically, miR-30a inhibited the expression of Ppargc1b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that miR-30a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS.

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References

  1. Karussis D. The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review. J Autoimmun 2014, 48–49: 134–142.

    Article  PubMed  Google Scholar 

  2. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012, 8: 647–656.

    Article  CAS  PubMed  Google Scholar 

  3. Ciccarelli O, Thompson A. Multiple sclerosis in 2015: Managing the complexity of multiple sclerosis. Nat Rev Neurol 2016, 12: 70–72.

    Article  CAS  PubMed  Google Scholar 

  4. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol 2015, 15: 545–558.

    Article  CAS  PubMed  Google Scholar 

  5. Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol 2015, 14: 406–419.

    Article  CAS  PubMed  Google Scholar 

  6. Cao L, He C. Polarization of macrophages and microglia in inflammatory demyelination. Neurosci Bull 2013, 29: 189–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bogie JF, Stinissen P, Hendriks JJ. Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol 2014, 128: 191–213.

    Article  CAS  PubMed  Google Scholar 

  8. Hu J, He H, Yang Z, Zhu G, Kang L, Jing X, et al. Programmed death ligand-1 on microglia regulates Th1 differentiation via nitric oxide in experimental autoimmune encephalomyelitis. Neurosci Bull 2016, 32: 70–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Henderson AP, Barnett MH, Parratt JD, Prineas JW. Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 2009, 66: 739–753.

    Article  PubMed  Google Scholar 

  10. Stys PK, Zamponi GW, van Minnen J, Geurts JJ. Will the real multiple sclerosis please stand up? Nat Rev Neurosci 2012, 13: 507–514.

    Article  CAS  PubMed  Google Scholar 

  11. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003, 3: 23–35.

    Article  CAS  PubMed  Google Scholar 

  12. Franco R, Fernandez-Suarez D. Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 2015, 131: 65–86.

    Article  CAS  PubMed  Google Scholar 

  13. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013, 16: 1211–1218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 2011, 11: 750–761.

    Article  CAS  PubMed  Google Scholar 

  15. Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal 2014, 26: 192–197.

    Article  CAS  PubMed  Google Scholar 

  16. Zhou S, Ding F, Gu X. Non-coding RNAs as emerging regulators of neural injury responses and regeneration. Neurosci Bull 2016, 32: 253–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-alpha-PU.1 pathway. Nat Med 2011, 17: 64–70.

    Article  CAS  PubMed  Google Scholar 

  18. Cardoso AL, Guedes JR, Pereira de Almeida L, Pedroso de Lima MC. miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production. Immunology 2012, 135: 73–88.

  19. O’Brien JH, Hernandez-Lagunas L, Artinger KB, Ford HL. MicroRNA-30a regulates zebrafish myogenesis through targeting the transcription factor Six1. J Cell Sci 2014, 127: 2291–2301.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Qu X, Zhou J, Wang T, Han J, Ma L, Yu H, et al. MiR-30a inhibits Th17 differentiation and demyelination of EAE mice by targeting the IL-21R. Brain Behav Immun 2016, 57: 193–199.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang N, Wang X, Huo Q, Sun M, Cai C, Liu Z, et al. MicroRNA-30a suppresses breast tumor growth and metastasis by targeting metadherin. Oncogene 2014, 33: 3119–3128.

    Article  CAS  PubMed  Google Scholar 

  22. Zhao M, Sun D, Guan Y, Wang Z, Sang D, Liu M, et al. Disulfiram and diphenhydramine hydrochloride upregulate miR-30a to suppress IL-17-associated autoimmune inflammation. J Neurosci 2016, 36: 9253–9266.

    Article  CAS  PubMed  Google Scholar 

  23. de Planell-Saguer M, Rodicio MC, Mourelatos Z. Rapid in situ codetection of noncoding RNAs and proteins in cells and formalin-fixed paraffin-embedded tissue sections without protease treatment. Nat Protoc 2010, 5: 1061–1073.

    Article  PubMed  Google Scholar 

  24. Yu Z, Sun D, Feng J, Tan W, Fang X, Zhao M, et al. MSX3 switches microglia polarization and protects from inflammation-induced demyelination. J Neurosci 2015, 35: 6350–6365.

    Article  CAS  PubMed  Google Scholar 

  25. Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Transcranial amelioration of inflammation and cell death after brain injury. Nature 2014, 505: 223–228.

    Article  CAS  PubMed  Google Scholar 

  26. Wei W, Wang X, Yang M, Smith LC, Dechow PC, Sonoda J, et al. PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. Cell Metab 2010, 11: 503–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Croasdell A, Duffney PF, Kim N, Lacy SH, Sime PJ, Phipps RP. PPARgamma and the innate immune system mediate the resolution of inflammation. PPAR Res 2015, 2015: 549691.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Juhas U, Ryba-Stanislawowska M, Szargiej P, Mysliwska J. Different pathways of macrophage activation and polarization. Postepy Hig Med Dosw (Online) 2015, 69: 496–502.

    Article  Google Scholar 

  29. Sanders P, De Keyser J. Janus faces of microglia in multiple sclerosis. Brain Res Rev 2007, 54: 274–285.

    Article  CAS  PubMed  Google Scholar 

  30. Moore CS, Rao VT, Durafourt BA, Bedell BJ, Ludwin SK, Bar–Or A, et al. miR–155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. Ann Neurol 2013, 74: 709–720.

    Article  CAS  PubMed  Google Scholar 

  31. Ponomarev ED, Veremeyko T, Weiner HL. MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS. Glia 2013, 61: 91–103.

    Article  PubMed  Google Scholar 

  32. Yu Y, Cao L, Yang L, Kang R, Lotze M, Tang D. microRNA 30A promotes autophagy in response to cancer therapy. Autophagy 2012, 8: 853–855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zou Z, Wu L, Ding H, Wang Y, Zhang Y, Chen X, et al. MicroRNA-30a sensitizes tumor cells to cis-platinum via suppressing beclin 1-mediated autophagy. J Biol Chem 2012, 287: 4148–4156.

    Article  CAS  PubMed  Google Scholar 

  34. Xie D, Shen F, He S, Chen M, Han Q, Fang M, et al. IL-1beta induces hypomyelination in the periventricular white matter through inhibition of oligodendrocyte progenitor cell maturation via FYN/MEK/ERK signaling pathway in septic neonatal rats. Glia 2016, 64: 583–602.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank the Netherlands Brain Bank for kindly providing the brain slices from MS patients. This work was supported by the International Cooperation and Exchange of the National Natural Science Foundation of China (81461138035), the National Natural Science Foundation of China (81371326, 31371068, and 31571066), and the National Key Research and Development Program of China (2016YFA0100802).

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  1. Xue Fang, Dingya Sun, and Zhihong Wang have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Molecular Neurobiology of the Ministry of Education and the Collaborative Innovation Center for Brain Science, Institute of Neuroscience, Second Military Medical University, Shanghai, 200433, China

    Xue Fang, Dingya Sun, Zhihong Wang, Zhongwang Yu, Weili Liu, Yingyan Pu, Dan Wang, Aijun Huang, Mingdong Liu, Zhenghua Xiang, Cheng He & Li Cao

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  1. Xue Fang
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Correspondence to Cheng He or Li Cao.

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Fang, X., Sun, D., Wang, Z. et al. MiR-30a Positively Regulates the Inflammatory Response of Microglia in Experimental Autoimmune Encephalomyelitis. Neurosci. Bull. 33, 603–615 (2017). https://doi.org/10.1007/s12264-017-0153-y

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  • DOI: https://doi.org/10.1007/s12264-017-0153-y

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