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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Figure 1

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IL-6 is selectively upregulated in the CSF of TM patients and correlates...
IL-6 is selectively upregulated in the CSF of TM patients and correlates with long-term disability. (A) Cytokine array was used to profile 42 inflammatory proteins in the CSF of 6 TM and 8 control patients. The mean value of each cytokine was defined for the control group, and fold induction was calculated for each TM patient. Inset: IL-6 immunohistochemistry was performed on the cervical spinal cord of a TM patient who died of respiratory failure; IL-6 expression colocalized with GFAP-positive astrocytes. Magnification, ×60. (B) Quantitative IL-6 levels in the CSF and serum of control (Con) and TM patients were determined by ELISA. Box plots represent the interquartile range, and the outliers shown are outside the fifth and ninety-fifth percentiles. Mean ± SEM for each group is indicated above each box. (C) Among TM patients, acute CSF IL-6 levels strongly correlated with sustained disability (as measured by EDSS). (D) CSF IL-6 levels strongly correlate with total NO metabolites during the acute phase of TM. (E) Total NO correlates with 14-3-3, a neuronal injury marker in TM patients. (F) Levels of 14-3-3 strongly correlate with sustained disability in TM patients. For panels C–F, correlation coefficients and statistical significance are shown. Intensity, chemiluminescent signal intensity.