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Open Access 01-12-2018 | Research

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury

Authors: Yue Zhou, Wei Guo, Zhenjie Zhu, Yuming Hu, Yingjie Wang, Xuejie Zhang, Wenjuan Wang, Nan Du, Tiancheng Song, Kaini Yang, Zongyu Guan, Yongjun Wang, Aisong Guo

Published in: Journal of Neuroinflammation | Issue 1/2018

Abstract

Background

Astrocytes act as immune effector cells with the ability to produce a wide array of chemokines and cytokines in response to various stimuli. Macrophage migration inhibitory factor (MIF) is inducibly expressed in injured spinal cord contributing to excessive inflammation that affects motor functional recovery. Unknown is whether MIF can facilitate inflammatory responses through stimulating release of chemokines from astrocytes following spinal cord injury.

Methods

Following the establishment of the contusion spinal cord injury rat model, the correlation of chemokine (C-C motif) ligand 5 (CCL5) expression with that of MIF was assayed by Western blot, ELISA, and immunohistochemistry. Immunoprecipitation was used to detect MIF interaction with membrane CD74 receptor. Intracellular signal transduction of MIF/CD74 axis was analyzed by transcriptome sequencing of primary astrocytes and further validated by treatment of various inhibitors. The effects of CCL5 released by astrocytes on macrophage migration were performed by transwell migration assay. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale.

Results

The protein levels of chemokine CCL5/RANTES were remarkably increased in the astrocytes of rat injured spinal cord, in parallel with the expression of MIF. Treatment of MIF inhibitor 4-IPP in the lesion sites resulted in a significant decrease of CCL5 protein levels. In vitro study revealed MIF was capable of facilitating CCL5 production of astrocytes through interaction with CD74 membrane receptor, and knockdown of this receptor attenuated such effects. Production of CCL5 in astrocytes was significantly blocked by inhibitor of c-Jun N-terminal kinase, rather than by those of ERK and P38. Recombinant CCL5 protein was found to be more effective in promoting migration of M2- compared to M1-type macrophages.

Conclusion

Collectively, these data reveal a novel function of MIF in regulation of CCL5 release from astrocytes, which in turn favors for recruitment of inflammatory cells to the injured site of the spinal cord, in association with activation of excessive inflammation.

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Gadani SP, Walsh JT, Lukens JR, Kipnis J. Dealing with danger in the CNS: the response of the immune system to injury. Neuron. 2015;87:47–62.CrossRefPubMedPubMedCentral

Babcock AA, Kuziel WA, Rivest S, Owens T. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci. 2003;23:7922–30.CrossRefPubMed

Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord. 2003;41:369–78.CrossRefPubMed

Rossi D. Astrocyte physiopathology: at the crossroads of intercellular networking, inflammation and cell death. Prog Neurobiol. 2015;130:86–120.CrossRefPubMed

Luo Y, Berman MA, Zhai Q, Fischer FR, Abromson-Leeman SR, Zhang Y, Kuziel WA, Gerard C, Dorf ME. RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes. Glia. 2002;39:19–30.CrossRefPubMed

Meeuwsen S, Persoon-Deen C, Bsibsi M, Ravid R, van Noort JM. Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. Glia. 2003;43:243–53.CrossRefPubMed

Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD. Differential activation of astrocytes by innate and adaptive immune stimuli. Glia. 2005;49:360–74.CrossRefPubMed

Falsig J, Porzgen P, Lund S, Schrattenholz A, Leist M. The inflammatory transcriptome of reactive murine astrocytes and implications for their innate immune function. J Neurochem. 2006;96:893–907.CrossRefPubMed

Marques RE, Guabiraba R, Russo RC, Teixeira MM. Targeting CCL5 in inflammation. Expert Opin Ther Targets. 2013;17:1439–60.CrossRefPubMed

10.

Vogel DY, Heijnen PD, Breur M, de Vries HE, Tool AT, Amor S, Dijkstra CD. Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation. J Neuroinflammation. 2014;11:23.CrossRefPubMedPubMedCentral

11.

Glabinski AR, Tuohy VK, Ransohoff RM. Expression of chemokines RANTES, MIP-1alpha and GRO-alpha correlates with inflammation in acute experimental autoimmune encephalomyelitis. Neuroimmunomodulation. 1998;5:166–71.CrossRefPubMed

12.

Oh JW, Schwiebert LM, Benveniste EN. Cytokine regulation of CC and CXC chemokine expression by human astrocytes. J Neuro-Oncol. 1999;5:82–94.

13.

Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003;3:791–800.CrossRefPubMed

14.

Chalimoniuk M, King-Pospisil K, Metz CN, Toborek M. Macrophage migration inhibitory factor induces cell death and decreases neuronal nitric oxide expression in spinal cord neurons. Neuroscience. 2006;139:1117–28.CrossRefPubMed

15.

Ogata A, Nishihira J, Suzuki T, Nagashima K, Tashiro K. Identification of macrophage migration inhibitory factor mRNA expression in neural cells of the rat brain by in situ hybridization. Neurosci Lett. 1998;246:173–7.CrossRefPubMed

16.

Koda M, Nishio Y, Hashimoto M, Kamada T, Koshizuka S, Yoshinaga K, Onodera S, Nishihira J, Moriya H, Yamazaki M. Up-regulation of macrophage migration-inhibitory factor expression after compression-induced spinal cord injury in rats. Acta Neuropathol. 2004;108:31–6.CrossRefPubMed

17.

Nishio Y, Koda M, Hashimoto M, Kamada T, Koshizuka S, Yoshinaga K, Onodera S, Nishihira J, Okawa A, Yamazaki M. Deletion of macrophage migration inhibitory factor attenuates neuronal death and promotes functional recovery after compression-induced spinal cord injury in mice. Acta Neuropathol. 2009;117:321–8.CrossRefPubMed

18.

Su Y, Wang Y, Zhou Y, Zhu Z, Zhang Q, Zhang X, Wang W, Gu X, Guo A, Wang Y. Macrophage migration inhibitory factor activates inflammatory responses of astrocytes through interaction with CD74 receptor. Oncotarget. 2017;8:2719–30.PubMed

19.

Dong Y, Benveniste EN. Immune function of astrocytes. Glia. 2001;36:180–90.CrossRefPubMed

20.

Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28:138–45.CrossRefPubMed

21.

Lin MS, Hung KS, Chiu WT, Sun YY, Tsai SH, Lin JW, Lee YH. Curcumin enhances neuronal survival in N-methyl-d-aspartic acid toxicity by inducing RANTES expression in astrocytes via PI-3K and MAPK signaling pathways. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35:931–8.CrossRef

22.

Gangwani MR, Noel RJ Jr, Shah A, Rivera-Amill V, Kumar A. Human immunodeficiency virus type 1 viral protein R (Vpr) induces CCL5 expression in astrocytes via PI3K and MAPK signaling pathways. J Neuroinflammation. 2013;10:136.CrossRefPubMedPubMedCentral

23.

Chehrehasa F, Cobcroft M, Young YW, Mackay-Sim A, Goss B. An acute growth factor treatment that preserves function after spinal cord contusion injury. J Neurotrauma. 2014;31:1807–13.CrossRefPubMed

24.

Liu J, Du L. PERK pathway is involved in oxygen-glucose-serum deprivation-induced NF-kB activation via ROS generation in spinal cord astrocytes. Biochem Biophys Res Commun. 2015;467:197–203.CrossRefPubMed

25.

Zhao Y, Wang Y, Gong J, Yang L, Niu C, Ni X, Wang Y, Peng S, Gu X, Sun C, Yang Y. Chitosan degradation products facilitate peripheral nerve regeneration by improving macrophage-constructed microenvironments. Biomaterials. 2017;134:64–77.CrossRefPubMed

26.

Kramer A, Green J, Pollard J Jr, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30:523–30.CrossRefPubMed

27.

Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995;12:1–21.CrossRefPubMed

28.

Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R. MIF signal transduction initiated by binding to CD74. J Exp Med. 2003;197:1467–76.CrossRefPubMedPubMedCentral

29.

Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007;13:587–96.CrossRefPubMed

30.

DeLeon-Pennell KY, Iyer RP, Ero OK, Cates CA, Flynn ER, Cannon PL, Jung M, Shannon D, Garrett MR, Buchanan W, et al. Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing. JCI Insight. 2017;2:14.

31.

Kim MO, Suh HS, Brosnan CF, Lee SC. Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and interferon-beta. J Neurochem. 2004;90:297–308.CrossRefPubMed

32.

Nakamichi K, Saiki M, Sawada M, Takayama-Ito M, Yamamuro Y, Morimoto K, Kurane I. Rabies virus-induced activation of mitogen-activated protein kinase and NF-kappaB signaling pathways regulates expression of CXC and CC chemokine ligands in microglia. J Virol. 2005;79:11801–12.CrossRefPubMedPubMedCentral

33.

Tanuma N, Sakuma H, Sasaki A, Matsumoto Y. Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol. 2006;112:195–204.CrossRefPubMed

34.

Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.CrossRefPubMedPubMedCentral

35.

Leyton-Jaimes MF, Kahn J, Israelson A. Macrophage migration inhibitory factor: a multifaceted cytokine implicated in multiple neurological diseases. Exp Neurol. 2018;301:83–91.CrossRefPubMed

36.

Bacher M, Schrader J, Thompson N, Kuschela K, Gemsa D, Waeber G, Schlegel J. Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Am J Pathol. 2003;162:11–7.CrossRefPubMedPubMedCentral

37.

An JH, Lee SY, Jeon JY, Cho KG, Kim SU, Lee MA. Identification of gliotropic factors that induce human stem cell migration to malignant tumor. J Proteome Res. 2009;8:2873–81.CrossRefPubMed

38.

Benedek G, Meza-Romero R, Jordan K, Keenlyside L, Offner H, Vandenbark AA. HLA-DRalpha1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection. J Neuroinflammation. 2015;12:123.CrossRefPubMedPubMedCentral

39.

Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994;179:1895–902.CrossRefPubMed

40.

David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011;12:388–99.CrossRefPubMed

41.

Thawer SG, Mawhinney L, Chadwick K, de Chickera SN, Weaver LC, Brown A, Dekaban GA. Temporal changes in monocyte and macrophage subsets and microglial macrophages following spinal cord injury in the Lys-Egfp-ki mouse model. J Neuroimmunol. 2013;261:7–20.CrossRefPubMed

42.

Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, et al. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity. 2006;25:595–606.CrossRefPubMedPubMedCentral

43.

Lue H, Dewor M, Leng L, Bucala R, Bernhagen J. Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74. Cell Signal. 2011;23:135–44.CrossRefPubMed

44.

Zhu G, Tang Y, Geng N, Zheng M, Jiang J, Li L, Li K, Lei Z, Chen W, Fan Y, et al. HIF-alpha/MIF and NF-kappaB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC. Neoplasia. 2014;16:168–79.CrossRefPubMedPubMedCentral

45.

Ishida Y, Kimura A, Kuninaka Y, Inui M, Matsushima K, Mukaida N, Kondo T. Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing. J Clin Invest. 2012;122:711–21.CrossRefPubMedPubMedCentral

46.

Keophiphath M, Rouault C, Divoux A, Clement K, Lacasa D. CCL5 promotes macrophage recruitment and survival in human adipose tissue. Arterioscler Thromb Vasc Biol. 2010;30:39–45.CrossRefPubMed

47.

Keepers TR, Gross LK, Obrig TG. Monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic-uremic syndrome. Infect Immun. 2007;75:1229–36.CrossRefPubMedPubMedCentral

48.

Liou JT, Yuan HB, Mao CC, Lai YS, Day YJ. Absence of C-C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model. Pain. 2012;153:1283–91.CrossRefPubMed

49.

Lee CM, Peng HH, Yang P, Liou JT, Liao CC, Day YJ. C-C chemokine ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury. Sci Rep. 2017;7:3698.CrossRefPubMedPubMedCentral

50.

Zhang B, Gensel JC. Is neuroinflammation in the injured spinal cord different than in the brain? Examining intrinsic differences between the brain and spinal cord. Exp Neurol. 2014;258:112–20.CrossRefPubMed

51.

Si Q, Kim MO, Zhao ML, Landau NR, Goldstein H, Lee S. Vpr- and Nef-dependent induction of RANTES/CCL5 in microglial cells. Virology. 2002;301:342–53.CrossRefPubMed

Title: Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury
Authors: Yue Zhou
Wei Guo
Zhenjie Zhu
Yuming Hu
Yingjie Wang
Xuejie Zhang
Wenjuan Wang
Nan Du
Tiancheng Song
Kaini Yang
Zongyu Guan
Yongjun Wang
Aisong Guo
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-018-1297-z

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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