A novel cell-cell signaling by microglial transmembrane TNF? with implications for neuropathic pain.

ABSTRACT: Neuropathic pain is accompanied by neuroimmune activation in dorsal horn of spinal cord. We have observed that in animal models this activation is characterized by an increased expression of transmembrane tumor necrosis factor ? (mTNF?) without the release of soluble tumor necrosis factor ? (sTNF?). Herein we report that the pain-related neurotransmitter peptide substance P (SP) increases the expression of mTNF? without the release of sTNF? from primary microglial cells. We modeled this interaction using an immortalized microglial cell line; exposure of these cells to SP also resulted in the increased expression of mTNF? but without any increase in the expression of the TNF-cleaving enzyme (TACE) and no release of sTNF?. In order to evaluate the biological function of uncleaved mTNF?, we transfected COS-7 cells with a mutant full-length TNF? construct resistant to cleavage by TACE. Coculture of COS-7 cells expressing the mutant TNF? with microglial cells led to microglial cell activation indicated by increased OX42 immunoreactivity and release of macrophage chemoattractant peptide 1 (CCL2) by direct cell-cell contact. These results suggest a novel pathway through which the release of SP by primary afferents activates microglial expression of mTNF?, establishing a feed-forward loop that may contribute to the establishment of chronic pain.

SUBMITTER: Zhou Z 

PROVIDER: S-EPMC2955857 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature