Divergent Roles for Tumor Necrosis Factor-α in the Brain

Abstract

Proinflammatory cytokines and chemokines have been implicated in the pathogenesis of several neurological and neurodegenerative disorders. Prominent among such factors is the pleiotropic cytokine, tumor necrosis factor (TNF)-alpha. Under normal physiological conditions, TNF-alpha orchestrates a diverse array of functions involved in immune surveillance and defense, cellular homeostasis, and protection against certain neurological insults. However, paradoxical effects of this cytokine have been observed. TNF-alpha is elicited in the brain following injury (ischemia, trauma), infection (HIV, meningitis), neurodegeneration (Alzheimer's, Parkinson's), and chemically induced neurotoxicity. The multifarious identity for this cytokine appears to be influenced by several mechanisms. Among the most prominent are the regulation of TNFalpha-induced NF-kappaB activation by adapter proteins such as TRADD and TRAF, and second, the heterogeneity of microglia and their distribution pattern across brain regions. Here, we review the differential role of TNF-alpha in response to brain injury, with emphasis on neurodegeneration, and discuss the possible mechanisms for such diverse and region-specific effects.

Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients

“…TNFa has been implicated in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and human immunodeficiency virus-related encephalopathy. 20 Additionally, the TNFa system is activated in diabetic polyneuropathy, which leads to increased microvascular permeability, hypercoagulability and even direct nerve damage. Improvement of diabetic polyneuropathy following suppression of TNFa has been shown in several animal models.…”

Tumor Necrosis Factor-α (TNF-α) Regulates Shedding of TNF-α Receptor 1 by the Metalloprotease-Disintegrin ADAM8: Evidence for a Protease-Regulated Feedback Loop in Neuroprotection

“…Tumor necrosis factor ␣ (TNF-␣) is a potent cytokine with beneficial as well as proinflammatory and neurotoxic effects in the CNS (for review, see Sriram and O'Callaghan, 2007). Its pleiotropic activities are mediated by two cell surface receptors, p55 (TNF-R1) and p75 (TNF-R2).…”

iRhoms in the brain – a new frontier?

“…Stefan F Lichtenthaler 1,2,3,4 , Bruce F O'Hara 5 , and Carl P Blobel 4,6,7 The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) orchestrates cell-cell interactions and has a key role in inflammation, development and in diseases such as Rheumatoid Arthritis and Cancer. ADAM17 is responsible for liberating the pro-inflammatory cytokine TNFa and most EGFR-ligands from their membrane anchor, thereby keeping a close reign on the TNFa-and EGFR signaling pathways.…”

“…There is mounting evidence that this depends, at least in part, on activation of the TNFa pathway. 4 Moving forward, it will be interesting to learn more about the functions of the iRhom2/ ADAM17-dependent production of soluble TNFa in TBI, AD and other brain diseases that could be exacerbated by inflammation. If the iRhom2/ ADAM17/TNFa pathway is indeed activated by brain injury or amyloid plaques, and if blocking components of this pathway can ameliorate or prevent the cognitive impairment associated with animal models of AD or TBI, then iRhom2 could become an attractive target to prevent cognitive decline caused by neuroinflammation.…”