Reducing inflammation through delivery of lentivirus encoding for anti-inflammatory cytokines attenuates neuropathic pain after spinal cord injury

JOURNAL OF CONTROLLED RELEASE

卷:290

Article

Park, Jonghyuck¹  Decker, Joseph T.¹  Smith, Dominique R.¹  Cummings, Brian J.^2,3  Anderson, Aileen J.^2,3  Shea, Lonnie D.^1,4 

[1] Univ Michigan, Dept Biomed Engn, 2200 Bonisteel Blvd,1119 Carl A Gerstacker Bldg, Ann Arbor, MI 48109 USA

[2] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92717 USA

[3] Univ Calif Irvine, Dept Phys Med & Rehabil, Irvine, CA USA

[4] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA

关键词: Spinal cord injury;    Neuropathic pain;    Gene delivery;    Immunoengineering;    Anti-inflammatory cytokine;   

DOI  :  10.1016/j.jconrel.2018.10.003

来源: Elsevier

【 摘 要 】

Recently, many clinical trials have challenged the efficacy of current therapeutics for neuropathic pain after spinal cord injury (SCI) due to their life-threatening side-effects including addictions. Growing evidence suggests that persistent inflammatory responses after primary SCI lead to an imbalance between anti-inflammation and pro-inflammation, resulting in pathogenesis and maintenance of neuropathic pain. Conversely, a variety of data suggest that inflammation contributes to regeneration. Herein, we investigated long-term local immunomodulation using anti-inflammatory cytokine IL-10 or IL-4-encoding lentivirus delivered from multichannel bridges. Multichannel bridges provide guidance for axonal outgrowth and act as delivery vehicles. Anti-inflammatory cytokines were hypothesized to modulate the pro-nociceptive inflammatory niche and promote axonal regeneration, leading to neuropathic pain attenuation. Gene expression analyses demonstrated that IL-10 and IL-4 decreased pro-nociceptive genes expression versus control. Moreover, these factors resulted in an increased number of pro-regenerative macrophages and restoration of normal nociceptors expression pattern. Furthermore, the combination of bridges with anti-inflammatory cytokines significantly alleviated both mechanical and thermal hypersensitivity relative to control and promoted axonal regeneration. Collectively, these studies highlight that immunomodulatory strategies target multiple barriers to decrease secondary inflammation and attenuate neuropathic pain after SCI.

【 授权许可】

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