IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis
Adam I. Kaplin, Deepa M. Deshpande, Erick Scott, Chitra Krishnan, Jessica S. Carmen, Irina Shats, Tara Martinez, Jennifer Drummond, Sonny Dike, Mikhail Pletnikov, Sanjay C. Keswani, Timothy H. Moran, Carlos A. Pardo, Peter A. Calabresi, Douglas A. Kerr
Adam I. Kaplin, Deepa M. Deshpande, Erick Scott, Chitra Krishnan, Jessica S. Carmen, Irina Shats, Tara Martinez, Jennifer Drummond, Sonny Dike, Mikhail Pletnikov, Sanjay C. Keswani, Timothy H. Moran, Carlos A. Pardo, Peter A. Calabresi, Douglas A. Kerr
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Research Article Neuroscience

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

Abstract

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.

Authors

Adam I. Kaplin, Deepa M. Deshpande, Erick Scott, Chitra Krishnan, Jessica S. Carmen, Irina Shats, Tara Martinez, Jennifer Drummond, Sonny Dike, Mikhail Pletnikov, Sanjay C. Keswani, Timothy H. Moran, Carlos A. Pardo, Peter A. Calabresi, Douglas A. Kerr

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IL-6 induces weakness with axonal degeneration and loss of myelin when i...
IL-6 induces weakness with axonal degeneration and loss of myelin when infused into the spinal subarachnoid space of adult rats. (A) We infused IL-6 via a subarachnoid spinal catheter into adult rats over a 7-day period. Control animals received saline through the spinal catheter, while another cohort of animals received intrathecal IL-6 and were also given the iNOS inhibitor aminoguanidine (AG) intraperitoneally for the length of the experiment beginning at day 0. *P < 0.05. (B) Pathologic specimens from IL-6–infused rat spinal cords exhibited reduced myelin staining and white matter vacuolation (asterisks). Scale bar: 20 μm. (C) White matter vacuoles (asterisks) were strongly NF positive, confirming the presence of axonal degeneration. Scale bar: 20 μm. (D and E) Plastic sections (1 μM) from IL-6–infused rat spinal cords revealed 2 pathologic features, seen principally in superficial white matter regions: (D) swollen axons with intact myelin (asterisks), consistent with axonal degeneration, and (E) demyelinated axons (arrows). Scale bar: 10 μm (D and E). (F) These pathologic features could also be seen in autopsy material from a patient with severe TM and high CSF IL-6 levels (1,997 pg/ml). Regions of demyelination (arrows) were seen throughout the cervical spinal cord both with H&E staining and with luxol fast blue (LFB), and there were areas of vacuolation within the white matter (asterisks), consistent with axonal degeneration. (G) Immunohistochemical analysis of the autopsy material also revealed axonal dysfunction as defined by disruption of NF staining and accumulation of APP, a marker of disrupted axonal transport.