Crosstalk between macrophages and astrocytes affects proliferation, reactive phenotype and inflammatory response, suggesting a role during reactive gliosis following spinal cord injury

Journal of Neuroinflammation

Bing Song¹  Xiaoqing Wei⁴  Jian Wang³  Bangfu Zhu⁴  Niels Haan² 

[1] Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, China;Neuroscience and Mental Health Research Institute, College of Biomedical and Life Sciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK;Institute of Neurosciences, Fourth Military Medical University, 169 West Changle Road, Xi’an 710032, China;Cardiff Institute of Tissue Engineering & Repair, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Heath Campus, Cardiff CF14 4XY, UK

关键词: Neuroinflammation;    Immune response;    Traumatic injury;    Spinal cord;    Glia;   

Others  :  1221967
DOI  :  10.1186/s12974-015-0327-3

 received in 2015-01-09, accepted in 2015-05-20,  发布年份 2015

【 摘 要 】

Background

Large-scale macrophage infiltration and reactive astrogliosis are hallmarks of early spinal cord injury (SCI) pathology. The exact nature of the macrophage response and relationship between these phenomena have not been explored in detail. Here, we have investigated these responses using a combination of in vivo SCI models, organotypic and primary cultures.

Methods

In vivo macrophage response was investigated using a contusive injury mouse model. Interactions between astrocytes and macrophages were studied in primary or organotypic cultures. Proliferation was assessed though MTT assay and nucleotide incorporation and gene expression changes through qPCR.

Results

Seven days following contusive SCI, a mixed M1/M2 macrophage response was seen in the injury site. Conditioned medium from primary M1, but not M2, macrophages are able to induce astrocyte proliferation in both organotypic spinal cord cultures and primary astrocytes. Soluble factors from M1 macrophages induce a reactive astrocyte gene expression pattern, whereas M2 factors inhibit expression of these genes. M2-stimulated astrocytes are also able to decrease both M1 and M2 macrophage proliferation and decrease TNFα production in M1 macrophages.

Conclusions

These results suggest a strong role of M1 macrophages in inducing reactive astrogliosis and the existence of an astrocyte-mediated negative feedback system in order to dampen the immune response. These results, combined with the poor outcomes of the current immunosuppressive steroid treatments in SCI, indicate the need for more targeted therapies, taking into account the significantly different effects of M1 and M2 macrophages, in order to optimise outcome.

【 授权许可】

   
2015 Haan et al.

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【 参考文献 】

• [1]Yong VW, Moumdjian R, Yong FP, Ruijs TC, Freedman MS, Cashman N, et al.: Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo. Proc Natl Acad Sci U S A. 1991, 88:7016-20.
• [2]Hurlbert RJ. The role of steroids in acute spinal cord injury: an evidence-based analysis. Spine (Phila Pa 1976). 2001;26:S39–46.
• [3]Short D: Is the role of steroids in acute spinal cord injury now resolved? Curr Opin Neurol. 2001, 14:759-63.
• [4]Greenhalgh AD, David S: Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death. J Neurosci. 2014, 34:6316-22.
• [5]Evans TA, Barkauskas DS, Myers JT, Hare EG, You JQ, Ransohoff RM, et al.: High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp Neurol. 2014, 254:109-20.
• [6]Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT: Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol. 1999, 158:351-65.
• [7]Wynn TA, Chawla A, Pollard JW: Macrophage biology in development, homeostasis and disease. Nature. 2013, 496:445-55.
• [8]Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, et al.: A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci U S A. 2009, 106:17475-80.
• [9]Campbell L, Saville CR, Murray PJ, Cruickshank SM, Hardman MJ: Local arginase 1 activity is required for cutaneous wound healing. J Invest Dermatol. 2013, 133:2461-70.
• [10]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, 16:1211-8.
• [11]Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG: Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009, 29:13435-44.
• [12]David S, Kroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011, 12:388-99.
• [13]Thawer SG, Mawhinney L, Chadwick K, de Chickera SN, Weaver LC, Brown A, et al.: 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.
• [14]Ahn M, Lee C, Jung K, Kim H, Moon C, Sim KB, et al.: Immunohistochemical study of arginase-1 in the spinal cords of rats with clip compression injury. Brain Res. 2012, 1445:11-9.
• [15]Shin T, Ahn M, Moon C, Kim S, Sim KB: Alternatively activated macrophages in spinal cord injury and remission: another mechanism for repair? Mol Neurobiol. 2013, 47:1011-9.
• [16]Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J: A pericyte origin of spinal cord scar tissue. Science. 2011, 333:238-42.
• [17]Yiu G, He Z: Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 2006, 7:617-27.
• [18]Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV: Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004, 24:2143-55.
• [19]Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, et al.: Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med. 2006, 12:829-34.
• [20]Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, et al.: STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008, 28:7231-43.
• [21]Kohta M, Kohmura E, Yamashita T: Inhibition of TGF-beta1 promotes functional recovery after spinal cord injury. Neurosci Res. 2009, 65:393-401.
• [22]Goldshmit Y, Frisca F, Pinto AR, Pebay A, Tang JK, Siegel AL, et al.: Fgf2 improves functional recovery-decreasing gliosis and increasing radial glia and neural progenitor cells after spinal cord injury. Brain Behav. 2014, 4:187-200.
• [23]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.
• [24]Zhu B, Zhao C, Young FI, Franklin RJ, Song B: B S. Isolation and long-term expansion of functional, myelinating oligodendrocyte progenitor cells from neonatal rat brain. Curr Protoc Stem Cell Biol. 2014, 31:2D.17.11-12D.17.15.
• [25]Haan N, Goodman T, Najdi-Samiei A, Stratford CM, Rice R, El Agha E, et al.: Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus. J Neurosci. 2013, 33:6170-80.
• [26]Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al.: Genomic analysis of reactive astrogliosis. J Neurosci. 2012, 32:6391-410.
• [27]Cekanaviciute E, Fathali N, Doyle KP, Williams AM, Han J, Buckwalter MS: Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. Glia. 2014, 62:1227-40.