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.

Tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the cerebrospinal fluid of patients with cervical myelopathy and lumbar radiculopathy

“…To our knowledge, reports of the cytokines in the CSF of patients with cervical myelopathy are also rare. Regarding other spinal cord disorders, Kaplin et al [9] indicated that the IL-6 levels were dramatically elevated in the CSF of patients with transverse myelitis and correlated with markers of tissue injury and clinical disability. In multiple sclerosis, Gruol and Nelson [5] reported indirect evidence that elevated IL-6 potentiated neural injury.…”

“…The highest possible JOA score-L is 29 points. The mean JOA score-L was 12.4 points (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. To evaluate the relationships between neurological deficits and the concentrations of the cytokines, the sum of motor disturbance and the sensory disturbance of JOA score-L (neurological deficits score) was calculated.…”

Cytokine Concentrations in the Cerebrospinal Fluid of Great Danes with Cervical Spondylomyelopathy

“…IL‐6 has various functions, including a role in the generation and propagation of chronic inflammation 26. Most studies have investigated IL‐6 in the setting of inflammatory SC disease or acute SC injury, and much less is known about its role in chronic compressive myelopathies 26, 27, 28. CSF IL‐6 was increased in people with cervical compressive myelopathy when compared to control individuals, but no correlation with disease severity or duration was found 17.…”

“…No studies have correlated CSF IL‐6 concentrations and SC signal changes. The SC parenchyma appears more sensitive than the brain tissue to the deleterious effects of IL‐6, with oligodendrocytes and axons being the primary targets of IL‐6 mediated cytotoxicity 27. It is possible that higher IL‐6 concentrations in CSM‐affected GDs with SC signal changes represent the presence of more severe tissue injury secondary to chronic inflammation compared to the affected GDs that do not show SC signal changes.…”

Acute inflammatory myelopathies

“…CSF IL-6 levels are markedly elevated in patients with ATM (Kaplin et al, 2005). Furthermore, there is a strong correlation between CSF IL-6 obtained at the time of acute clinical evaluation and long-term disability.…”