Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory molecule, which upon engagement with its cognate receptors on target cells, triggers downstream signaling cascades that control a number of cellular processes related to cell viability, gene expression, ion homeostasis, and synaptic integrity. In the central nervous system (CNS), TNF-alpha is produced by brain-resident astrocytes, microglia, and neurons in response to numerous intrinsic and extrinsic stimuli. This review will summarize the key events that lead to TNF-alpha elaboration in the CNS, and the effects that these inflammatory signals impart on neuronal signaling in the context of homeostasis and neuropathology.

Figure 1. TNF-α receptor signaling cascade

Binding of TNF-α to either of its cognate receptor subtypes can initiate apoptosis through TRADD domain activation or lead to the initiation of the NFκB and JNK signaling pathways. These signaling cascades can then result in activation/repression of key transcriptional targets and/or alterations in cellular physiology and viability.

Figure 2. TNF-α can modulate the activity of a number of neuronal ion channels

The activation of signaling cascades downstream of TNF-R activation leads to several alterations in ionic homeostasis. The known effects of the cytokine on specific neuronal channels are depicted.

Figure 3. Proposed feed-forward loop underlying AD pathogenesis

The accumulation of Aβ can induce microglial activation and the production of TNF-α. Furthermore, TNF-α has been shown to elicit several neuronal responses, including the heightened generation of Aβ. This feed-forward process is shown in a loop diagram. The resolution of which, through TNF-α signaling interventions, could result in the amelioration of Alzheimer’s disease pathology.