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Review
. 2022 Jun 28;23(13):7191.
doi: 10.3390/ijms23137191.

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

Yi-Wen Duan  1 , Shao-Xia Chen  2 , Qiao-Yun Li  1 , Ying Zang  1
Affiliations
Review

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

Yi-Wen Duan et al. Int J Mol Sci. .

Abstract

The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α-necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α-necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.

Keywords: necroptosis; neuroinflammation; neuropathic pain; tumor necrosis factor-alpha (TNF-α).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Tumor necrosis factor-alpha (TNF-α)/TNF receptor 1 (TNFR1)-mediated inflammatory response and cell death pathways. The binding of TNF-α to TNFR1 triggers inflammatory responses, apoptosis and necroptosis. Ubiquitination of receptor interacting protein kinase 1 (RIPK1) promotes cell survival and induces an inflammatory response by activating the NF-κB, p38 MAPK, JNK and ERK signalling pathways. If caspase-8 is present in cells, deubiquitination of RIPK1 results in the formation of either complex IIa or complex IIb, leading to RIPK1-independent apoptosis (RIA) or RIPK1-dependent apoptosis (RDA), respectively. If caspase-8 is absent, necroptosis is initiated, in which RIPk1, receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein play a key role.
Figure 2
Figure 2
Potential mechanisms underlying peripheral and central sensitization via TNF-α or the TNF-α–necroptosis pathway in neuropathic pain. TNF-α regulates voltage-gated sodium channels (VGSCs) to sensitize primary afferents in the peripheral nervous system, affects excitatory and inhibitory synaptic transmissions in central nervous system (CNS), and evokes positive feedback between TNF-α and microglial activation to induce neuroinflammation, thus facilitating pain transmission, adverse pain-associated emotional reactions and cognitive deficits. TNF-α-triggered necroptosis in the dorsal root ganglia (DRG), spinal cord and supraspinal region may be one of the key factors for inducing neuroimmune responses in neuropathic pain.
Figure 3
Figure 3
Global trends in the publication of necroptosis-related articles in the field of neuroscience analyzed via bibliometric analysis. (A) The number of articles published worldwide shows a steady upward trend. (B) The key nodes of necroptosis research [65,141,142,143,144,145].
Figure 4
Figure 4
Co-occurrence network of keywords in necroptosis research established using the VOSviewer software. Four categories of necroptosis-related keywords are shown in red, blue, green and yellow. The red clusters are largest, and ‘necroptosis’ constitutes the largest node. Keywords associated with neuroinflammation and neurodegeneration such as ‘inflammation’, ‘oxidative stress’, ‘activation’ and ‘neurodegeneration’ are also mentioned.
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