Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor

Abstract

Several observations suggest that tumour necrosis factor (TNF) plays a role in demyelination, although direct evidence for this is lacking. We have examined ultrastructurally rat sciatic nerves injected with TNF-alpha or TNF-beta: the effects of the two cytokines were found to be qualitatively similar. One day after injection nerves were oedematous and contained many inflammatory cells. Leucocytes were adherent to the walls of endoneurial vessels and sometimes were packed into the sub-endothelial layer apparently occluding the vascular lumen. Occasional myelinated axons were associated with macrophages and showed signs of myelin damage. By 3 days the inflammatory changes had diminished: some axons were degenerating or demyelinating. By 6-7 days, the vascular changes had resolved, and the endoneurium contained significant numbers of demyelinating and degenerating axons. Control nerves, which received injections of vehicle, showed no vascular changes and either no, or significantly fewer, degenerating or demyelinating axons. We conclude that the intraneural injection of TNF produces inflammatory vascular changes within the endoneurium, together with demyelination and axonal degeneration. We have also observed demyelination and degeneration in a preliminary study of the effects of TNF-alpha in mice. These findings may be relevant to the pathogenesis of demyelinating diseases such as Guillain-Barré syndrome.

Nucleus pulposus inhibits the axonal outgrowth of cultured dorsal root ganglion cells

“…Nucleus pulposus is similar in its constitution to cartilage, and it is known that axonal outgrowth is inhibited by cartilage-related molecules such as chondroitin sulphate, proteoglycan, agglutinin, chondroitin-6-sulphate and keratan sulfate [6,17,29,30]. However, there are also cytokines related to chondrocytes that may induce an inhibition of axonal outgrowth and regeneration of peripheral nerves as well as being neurotoxic in vivo [5,8,14,19,26,33]. Since such cytokines, IL-1β, IL-6 and TNF-α, may be found in disc herniation tissue and are known to be present in disc cell cultures, it may seem reasonable that such substances might be responsible for the effects on the cultured nerve cells [9,19,31].…”

The biochemical, histopathological and clinical comparison of the neuroprotective effects of subcutaneous adalimumab and intravenous methylprednisolone in an experimental compressive spinal cord trauma model

“…TNF-α facilitated the initiation of a local immune reaction in nerves. This cytokine causes damage in the blood-nerve barrier and has a cytotoxic effect on the vascular endothelium and increases vascular permeability (58,66). It therefore facilitates the passage of factors in the circulation such as immunoglobulins, cytokines and complements to the nerve tissue (31,74).…”

Identification of a microglia phenotype supportive of remyelination

“…In contrast, remyelination is also seriously delayed and affected when microglia/macrophages are not present (Kotter et al, 2005;Li et al, 2005). Genetic ablation of the two classical proinflammatory cytokines, tumor necrosis factor alpha (TNFa) and interleukin-1 beta (IL-1b), which after application in the CNS cause neuroinflammation and subsequent demyelination (Ferrari et al, 2004;Redford et al, 1995), had no effect on demyelination in the cuprizone model, but significantly impeded remyelination due to inadequate recruitment and differentiation of OPCs (Arnett et al, 2001;Mason et al, 2001). This clearly outlines the complex nature of the relationship between inflammation and remyelination.…”