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Local Injection of Lenti–BDNF at the Lesion Site Promotes M2 Macrophage Polarization and Inhibits Inflammatory Response After Spinal Cord Injury in Mice

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Abstract

There is much evidence to suggest that brain-derived neurotrophic factor (BDNF) is a prominent candidate in promoting neuroprotection, axonal regeneration, and synaptic plasticity following spinal cord injury (SCI). Although some evidence indicates that BDNF has potent anti-oxidative effects and may be involved in the regulation of the immune response, the effects of BDNF in the inflammatory response during the course of secondary damage after SCI is still unclear. The present study was designed to investigate the effects of BDNF with a special focus on their effect on macrophage polarization after SCI. Adult C57 mice underwent T10 spinal cord clip compression injury and received lenti-BDNF vector injections at the epicenter of the lesion site. Four days later, total BDNF levels were greatly increased in animals that received lenti-BDNF injections. Confocal imaging showed that more than 80 % of the lenti-virus infected cells were CD11b-positive macrophages. In addition, the expression of arginase-1 and CD206 (associated with M2 macrophage phenotype) significantly increased in the animals that received lenti-BDNF injections compared with those that received lenti-EGFP injections. On the contrary, the expression of CD16/32 and inducible nitric oxide synthase (M1 phenotype marker) was down-regulated as demonstrated using flow cytometry and immunohistochemistry. Furthermore, the production of interleukin 1β and tumor necrosis factor alpha was significantly reduced whereas the levels of interleukin 10 and interleukin 13 were elevated in subjects that received lenti-BDNF vector injections. The time course of functional recovery revealed that gradual recovery was observed in the subacute phase in lenti-BDNF group, little improvement was observed in lenti-EGFP group. At the axonal level, significant retraction of the CST axons were observed in lenti-EGFP injected animals relative to lenti-BDNF group by biotinylated dextran amine tracing. In addition, compared to lenti-BDNF group markedly demyelination was observed in the lenti-EGFP group using luxol fast blue staining. In conclusion, we found that BDNF could promote the shift of M1 to M2 phenotype and ameliorate the inflammatory microenvironment. Furthermore, the roles of BDNF in immunity modulation may enhance neuroprotective effects and partially contribute to the locomotor functional recovery after SCI.

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Acknowledgments

This work was supported by the Natural Scientific Research funds of China (No. 81371345) and Beijing Nova program (XX2013059). We thank Ms. Shan-shan Wang and Ms. Yan Zhang for their technical assistance.

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We certify that we have participated sufficiently in the work to take public responsibility for the appropriateness of the experimental design and method, and the collection, analysis, and interpretation of the data.

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Authors and Affiliations

  1. Graduate School, The Third Military Medical University, Chongqing, 400038, China

    Xin-Chao Ji & Ru-Xiang Xu

  2. The Affiliated Bayi Brain Hospital, The Military General Hospital of Beijing, PLA, Beijing, 100700, China

    Xin-Chao Ji, Yuan-Yuan Dang, Zhao-Tao Wang, Mou Gao, Yi Yang, Hong-Tian Zhang & Ru-Xiang Xu

  3. The Neurosurgical Research Center of Beijing Military Region PLA, Beijing, 100700, China

    Hong-Tian Zhang & Ru-Xiang Xu

  4. Medical Administration Department, The Military General Hospital of Beijing, PLA, Beijing, 100700, China

    Hong-Yan Gao

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  1. Xin-Chao Ji
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Correspondence to Hong-Tian Zhang or Ru-Xiang Xu.

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Ji, XC., Dang, YY., Gao, HY. et al. Local Injection of Lenti–BDNF at the Lesion Site Promotes M2 Macrophage Polarization and Inhibits Inflammatory Response After Spinal Cord Injury in Mice. Cell Mol Neurobiol 35, 881–890 (2015). https://doi.org/10.1007/s10571-015-0182-x

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  • DOI: https://doi.org/10.1007/s10571-015-0182-x

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