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Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury

Abstract

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3−/−, Nes-Socs3−/−). Reactive astrocytes in Nes-Stat3−/− mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3−/− mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.

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Figure 1: Migration of reactive astrocytes and compaction of inflammatory cells in wild-type mice.
Figure 2: Compaction of inflammatory cells by reactive astrocytes and functional recovery were limited in Nes-Stat3−/− mice after SCI.
Figure 3: Enhanced activation of Stat3, prompt compaction of inflammatory cells and marked functional improvement in Nes-Socs3−/− mice.
Figure 4: Involvement of Stat3 signaling in the development of reactive gliosis in vivo, the migration of reactive astrocytes in vitro and the transcriptional activity of LIV1.

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References

  1. Silver, J. & Miller, J.H. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156 (2004).

    Article  CAS  Google Scholar 

  2. Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med. 10, 48–54 (2004).

    Article  Google Scholar 

  3. Sano, S. et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 18, 4657–4668 (1999).

    Article  CAS  Google Scholar 

  4. Hirano, T., Ishihara, K. & Hibi, M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548–2556 (2000).

    Article  CAS  Google Scholar 

  5. Sriram, K., Benkovic, S.A., Hebert, M.A., Miller, D.B. & O'Callaghan, J.P. Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J. Biol. Chem. 279, 19936–19947 (2004).

    Article  CAS  Google Scholar 

  6. Kerr, B.J. & Patterson, P.H. Potent pro-inflammatory actions of leukemia inhibitory factor in the spinal cord of the adult mouse. Exp. Neurol. 188, 391–407 (2004).

    Article  CAS  Google Scholar 

  7. Xia, X.G., Hofmann, H.D., Deller, T. & Kirsch, M. Induction of STAT3 signaling in activated astrocytes and sprouting septal neurons following entorhinal cortex lesion in adult rats. Mol. Cell. Neurosci. 21, 379–392 (2002).

    Article  CAS  Google Scholar 

  8. Klein, M.A. et al. Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19, 227–233 (1997).

    Article  CAS  Google Scholar 

  9. Frisen, J., Johansson, C.B., Torok, C., Risling, M. & Lendahl, U. Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J. Cell Biol. 131, 453–464 (1995).

    Article  CAS  Google Scholar 

  10. Johansson, C.B., Lothian, C., Molin, M., Okano, H. & Lendahl, U. Nestin enhancer requirements for expression in normal and injured adult CNS. J. Neurosci. Res. 69, 784–794 (2002).

    Article  CAS  Google Scholar 

  11. Takeda, K. et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161, 4652–4660 (1998).

    CAS  PubMed  Google Scholar 

  12. Betz, U.A., Vosshenrich, C.A., Rajewsky, K. & Muller, W. Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination. Curr. Biol. 6, 1307–1316 (1996).

    Article  CAS  Google Scholar 

  13. Gao, Q. et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc. Natl. Acad. Sci. USA 101, 4661–4666 (2004).

    Article  CAS  Google Scholar 

  14. Kawamoto, S. et al. A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre-mediated recombination. FEBS Lett. 470, 263–268 (2000).

    Article  CAS  Google Scholar 

  15. Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739–743 (2004).

    Article  CAS  Google Scholar 

  16. Kubo, M., Hanada, T. & Yoshimura, A. Suppressors of cytokine signaling and immunity. Nat. Immunol. 4, 1169–1176 (2003).

    Article  CAS  Google Scholar 

  17. Faber-Elman, A., Solomon, A., Abraham, J.A., Marikovsky, M. & Schwartz, M. Involvement of wound-associated factors in rat brain astrocyte migratory response to axonal injury: in vitro simulation. J. Clin. Invest. 97, 162–171 (1996).

    Article  CAS  Google Scholar 

  18. Yamashita, S. et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature 429, 298–302 (2004).

    Article  CAS  Google Scholar 

  19. Penkowa, M., Giralt, M., Thomsen, P.S., Carrasco, J. & Hidalgo, J. Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes. J. Neurotrauma 18, 447–463 (2001).

    Article  CAS  Google Scholar 

  20. Penkowa, M., Carrasco, J., Giralt, M., Moos, T. & Hidalgo, J. CNS wound healing is severely depressed in metallothionein I- and II-deficient mice. J. Neurosci. 19, 2535–2545 (1999).

    Article  CAS  Google Scholar 

  21. Penkowa, M. et al. Astrocyte-targeted expression of IL-6 protects the CNS against a focal brain injury. Exp. Neurol. 181, 130–148 (2003).

    Article  CAS  Google Scholar 

  22. Lacroix, S., Chang, L., Rose-John, S. & Tuszynski, M.H. Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth. J. Comp. Neurol. 454, 213–228 (2002).

    Article  CAS  Google Scholar 

  23. Menet, V., Prieto, M., Privat, A. & Gimenezy Ribotta, M. Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc. Natl. Acad. Sci. USA 100, 8999–9004 (2003).

    Article  CAS  Google Scholar 

  24. Bush, T.G. et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23, 297–308 (1999).

    Article  CAS  Google Scholar 

  25. Faulkner, J.R. et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24, 2143–2155 (2004).

    Article  CAS  Google Scholar 

  26. Ozawa, Y. et al. Downregulation of STAT3 activation is required for presumptive rod photoreceptor cells to differentiate in the postnatal retina. Mol. Cell. Neurosci. 26, 258–270 (2004).

    Article  CAS  Google Scholar 

  27. Scheff, S.W., Rabchevsky, A.G., Fugaccia, I., Main, J.A. & Lumpp, J.E., Jr. Experimental modeling of spinal cord injury: characterization of a force-defined injury device. J. Neurotrauma 20, 179–193 (2003).

    Article  Google Scholar 

  28. Basso, D.M., Beattie, M.S. & Bresnahan, J.C. Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp. Neurol. 139, 244–256 (1996).

    Article  CAS  Google Scholar 

  29. Okano, H.J. & Darnell, R.B. A hierarchy of Hu RNA binding proteins in developing and adult neurons. J. Neurosci. 17, 3024–3037 (1997).

    Article  CAS  Google Scholar 

  30. Sanai, N. et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740–744 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, the General Insurance Association in Japan, Terumo Foundation Life Science Foundation (to H.O.), and a Grant-in-Aid for the 21st century COE program, Keio Gijuku Academic Development Funds.

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Authors and Affiliations

Authors

Contributions

S.O. performed most of the experiments to characterize mouse phenotypes. M.N. instructed group members about experimental processes. H.K. helped prepare the manuscript. T.M. and T.S. maintained and prepared knockout mice. K.I. and J.Y. prepared spinal cord–injured animals. A.Y. provided Nes-Socs3−/− mice. Y.I. advised experiments by S.O. Y.T. and H.O. designed experiments and prepared the manuscript.

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Correspondence to Hideyuki Okano.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Neuronal cell loss and ratio of pStat3 astrocytes. (PDF 501 kb)

Supplementary Fig. 2

Dividing inflammatory cells fill the lesion. (PDF 454 kb)

Supplementary Fig. 3

Generation of Nes-Stat3−/− mice and identification of Cre-mediated cells after SCI. (PDF 190 kb)

Supplementary Fig. 4

The effect of Stat3 on oligodendrocytes after SCI. (PDF 296 kb)

Supplementary Fig. 5

Quantification of regenerative fibers using anti-GAP 43 staining. (PDF 410 kb)

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Okada, S., Nakamura, M., Katoh, H. et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12, 829–834 (2006). https://doi.org/10.1038/nm1425

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