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Multiplex Epigenome Editing of Dorsal Root Ganglion Neuron Receptors Abolishes Redundant Interleukin 6, Tumor Necrosis Factor Alpha, and Interleukin 1β Signaling by the Degenerative Intervertebral Disc.

Authors
  • Stover, Joshua D1
  • Farhang, Niloofar1
  • Lawrence, Brandon2
  • Bowles, Robby D1, 2
  • 1 Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah.
  • 2 Department of Orthopaedics, University of Utah, Salt Lake City, Utah.
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Sep 01, 2019
Volume
30
Issue
9
Pages
1147–1160
Identifiers
DOI: 10.1089/hum.2019.032
PMID: 31056946
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Back pain is the leading cause of disability worldwide and contributes to significant socioeconomic impacts. It has been hypothesized that the degenerative intervertebral disc (IVD) contributes to back pain by sensitizing nociceptive neurons innervating the IVD to stimuli that would not be painful to healthy patients. However, the inflammatory signaling networks mediating this sensitization remain poorly understood. A better understanding of the underlying mechanisms of degenerative IVD-induced changes in nociception is required to improve the understanding and treatment of back pain. Toward these ends, a novel in vitro model was developed to investigate degenerative IVD-induced changes in dorsal root ganglion (DRG) neuron activation by measuring DRG neuron activity following neuron seeding on human degenerative IVD tissue collected from patients undergoing surgical treatment for back pain. Lentiviral clustered regularly interspaced palindromic repeat (CRISPR) epigenome editing vectors were built to downregulate the inflammatory receptors TNFR1, IL1R1, and IL6st in DRG neurons in single- and multiplex. Multiplex CRISPR epigenome editing of inflammatory receptors demonstrated that degenerative IVD tissue drives thermal sensitization through the simultaneous and redundant signaling of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and IL-1β. This work elucidates redundant signaling pathways in neuron interactions with the degenerative IVD and suggests the need for multiplex targeting of IL-6, TNF-α, and IL-1β for pain modulation in the degenerative IVD.

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