TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord

Abstract

Objectives: The purpose of the current study was to evaluate changes in tumor necrosis factor-alpha (TNF-alpha ) and TNF-alpha receptor 1 (p55 receptor) using double fluorescent immunohistochemistry in glial and neural cells in the dorsal root ganglion and spinal cord after sciatic nerve injury in mice. SUMMARY OF BACKGROUND DATA.: TNF-alpha is a primary mediator of the inflammatory response and is primarily synthesized and released in the nervous system by macrophages and Schwann cells following peripheral nerve injury. TNF-alpha is also released from astrocytes and microglia in the central nervous system, where it plays a crucial role in the pathophysiology of injury.

Methods: Sixteen female mice were used. Under anesthesia, the left sciatic nerve was crushed. At 3, 5, and 14 days after surgery, the spinal cord at the level of L5 and the left L5 DRG were removed and processed for immunohistochemistry. Tissue sections were double stained with antibodies to either glial fibrillary acidic protein (GFAP; marker for astrocytes or satellite cells) or NeuN (marker for neurons), and TNF or p55 receptor. RESULTS.: In the dorsal root ganglion, GFAP-immunoreactive (IR) satellite cells became evident after injury and were also immunoreactive for both TNF-alpha and p55 receptor. Dorsal root ganglion neurons expressed p55 receptor after injury. TNF-alpha and GFAP-IR satellite cells surrounded p55-IR neurons. Furthermore, the number of GFAP-IR astrocytes dramatically increased in the spinal cord after nerve injury, and some astrocytes were also TNF-alpha -IR and p55 receptor-IR. TNF-alpha -1R astrocytes were seen around p55 receptor-IR neurons.

Conclusions: These data demonstrate that upregulation of glial TNF-alpha is associated with the expression of the p55 receptor on adjacent neurons. This association may have induced the expression of several cytokines and immediate early genes in dorsal root ganglion and spinal cord neurons via the TNF signaling pathway. These findings may be related to the pathogenesis of neuropathic pain.