Full-length membrane-bound tumor necrosis factor-α acts through tumor necrosis factor receptor 2 to modify phenotype of sensory neurons

Abstract

Neuropathic pain resulting from spinal hemisection or selective spinal nerve ligation is characterized by an increase in membrane-bound TNF alpha (mTNFα) in spinal microglia without detectable release of soluble TNF alpha (sTNFα). In tissue culture, we showed that full length transmembrane cleavage-resistant TNFα (crTNFα) construct can act through cell-cell contact to activate neighboring microglia. We undertook the current study to test the hypothesis that mTNFα expressed in microglia might also affect the phenotype of primary sensory afferents, by determining the effect of crTNFα expressed from COS-7 cells on gene expression in primary DRG neurons. Co-culture of DRG neurons with crTNFα-expressing COS-7 cells resulted in a significant increase in the expression of voltage gated sodium channel isoforms NaV1.7 and NaV1.8, and voltage gated calcium channel subunit CaV3.2 at both mRNA and protein levels, and enhanced CCL2 expression and release from the DRG neurons. Exposure to sTNFα only produced an increase in CCL2 expression and release. Treatment of the cells with an siRNA against TNFR2 significantly reduced crTNFα-induced gene expression changes in DRG neurons while administration of CCR2 inhibitor had no significant effect on crTNFα-induced increase in gene expression and CCL2 release in DRG neurons. Taken together, the results suggest that mTNFα expressed in spinal microglia can facilitate pain signaling by up-regulating expression of cation channels and CCL2 in DRG neurons in a TNFR2 dependent manner.

Modulation of Voltage‐Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor‐1 and Receptor‐2 in Small DRG Neurons of Rats

“…The coexpression of TNFR and NaV isoforms has been shown for NaV1.7 in DRG neurons and chromaffin cells [ 30 ]. In addition, the expression of TNFR-2 has been shown to be closely related to NaV1.7 and NaV1.8 expression in sensory neurons, which may explain the predominant responding rates of D145 compared to R32W [ 31 ]. This effect may be important in the initial phase of inflammatory and neuropathic pain but may be superimposed by the changes in the pattern of expression of TNFR-1 and TNFR-2 after nerve injury and explain the effects of TNFR-1 and TNFR-2 seen in other studies, especially after nerve injury [ 6 , 25 ].…”

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

“…Importantly, these second messenger pathways can exert their effect by acting on ion channels. 143 – 147 For example, protein kinases such as adenosine monophosphate-activated protein kinase (AMPK), mitogen-activated protein kinase, protein kinase A (PKA), and PKC have all been shown to be involved in CIPN. 121 , 143 , 148 Concomitant administration of the oral hypoglycemic and AMPK activator metformin to mice with antineoplastics prevented development of mechanical hypersensitivity; such occlusion could result from either (1) mitogen-activated protein kinase-dependent changes in trafficking and/or phosphorylation or (2) AMPK-dependent phosphorylation of ion channels.…”

Effect of intermittent normobaric hyperoxia for treatment of neuropathic pain in Chinese patients with spinal cord injury

“…21 Transmembrane tumor necrosis factor-α increases hypersensitivity of phenotype of sensory neurons and activate microglia. 32,33 However, soluble tumor necrosis factor-α does not have that function. Third, normobaric hyperoxia can increase antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase).…”