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

作者：Zhou Zhigang; Peng Xiangmin; Hagshenas Jafar; Insolera Ryan; Fink David J^*; Mata Marina

来源：Pain, 2010, 151(2): 296-306.

DOI：10.1016/j.pain.2010.06.017

• Neuropathic pain
• Microglia
• Tumor necrosis factor
• Substance P
• CCL2

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 alpha (mTNF alpha) without the release of soluble tumor necrosis factor alpha (sTNF alpha). Herein we report that the pain-related neurotransmitter peptide substance P (SP) increases the expression of mTNF alpha without the release of sTNF alpha 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 alpha but without any increase in the expression of the TNF-cleaving enzyme (TACE) and no release of sTNF alpha. In order to evaluate the biological function of uncleaved mTNF alpha, we transfected COS-7 cells with a mutant full-length TNF alpha construct resistant to cleavage by TACE. Coculture of COS-7 cells expressing the mutant TNF alpha 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 alpha, establishing a feed-forward loop that may contribute to the establishment of chronic pain. Published by Elsevier B. V. on behalf of International Association for the Study of Pain.

• 出版日期2010-11