PD Guide

Neuroimmune Signaling Pathways

neuroimmunology
Neuroinflammatory Responses, Neuroimmune Function, Targeting Neuroimmune Dysfunction

TNF-alpha (tumor necrosis factor-alpha) signaling is involved in immune surveillance and defense, cellular homeostasis, and protection against neurological insults. In the brain, TNF regulates inflammation and injury responses through microglial and astrocyte activation, as well as several other important functions, including blood-brain barrier permeability, febrile responses, glutamatergic transmission, and synaptic plasticity and scaling.

The TNF receptor TNFR2 is expressed in the brain and activates cIAPs and NF-kappaB signaling to prevent cell death and promote further immune responses, including elevated inflammation. Post mortem analysis has demonstrated increase in the p65 NF-kappaB transcription factor in dopaminergic neurons of the substantia nigra in the PD brain. However, the function of this increased NF-kappaB activation remains unclear. It may act as an initial protective response against internal stress such as oxidative stress and mitochondrial dysfunction, but after prolonged activation may lead to damaging neuroinflammation (Mattson and Meffert, 2006; Memet, 2006).

TNF is associated with other neurodegenerative diseases in addition to PD, including multiple sclerosis, ischemia, and Alzheimer’s disease. TNF levels are elevated in PD patients, and post mortem analysis shows the highest levels of TNF in areas of dopaminergic cell death from PD. Pre-clinical research models also confirm upregulation of TNF-alpha, and risk analysis of TNF and TNFR polymorphisms indicates an association with PD susceptibility (Sriran and O'Callaghan, 2007; McCoy and Tansey, 2008).

Reference: 
Mattson MP, Meffert MK. Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ. 2006;13(5):852-60.
Mémet S. NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol. 2006;72(9):1180-95.
Sriram K, O'Callaghan JP. Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol. 2007;2(2):140-53.
McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. Journal of neuroinflammation. 2008;5:45.
Reply