Full-length membrane bound TNF alpha acts through TNF receptor 2 to modify the phenotype of sensory neurons

• Published in: Pain (Amsterdam) Vol. 154; no. 9; pp. 1778 - 1782
• Main Authors: Wu, Zetang, Wang, Shiyong, Gruber, Sandy, Mata, Marina, Fink, David J.
• Format: Journal Article
• Language: English
• Published: 24.05.2013
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2013.05.038

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 ( cr TNFα) 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 cr TNFα expressed from COS-7 cells on gene expression in primary DRG neurons. Co-culture of DRG neurons with cr TNFα-expressing COS-7 cells resulted in a significant increase in the expression of voltage gated sodium channel isoforms Na V 1.7 and Na V 1.8, and voltage gated calcium channel subunit Ca V 3.2 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 cr TNFα-induced gene expression changes in DRG neurons while administration of CCR2 inhibitor had no significant effect on cr TNFα-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.