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J Control Release. 2018 Nov 28;290:88-101. doi: 10.1016/j.jconrel.2018.10.003. Epub 2018 Oct 6.

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

Author information

1
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
2
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA; Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA.
3
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: ldshea@umich.edu.

Abstract

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.

KEYWORDS:

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

PMID:
30296461
PMCID:
PMC6240362
[Available on 2019-11-28]
DOI:
10.1016/j.jconrel.2018.10.003

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