A novel cell-cell signaling by microglial transmembrane TNFα with implications for neuropathic pain.
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 α (mTNFα) without the release of soluble tumor necrosis factor α (sTNFα). Herein we report that the pain-related neurotransmitter peptide substance P (SP) increases the expression of mTNFα without the release of sTNFα 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 mTNFα but without any increase in the expression of the TNF-cleaving enzyme (TACE) and no release of sTNFα. In order to evaluate the biological function of uncleaved mTNFα, we transfected COS-7 cells with a mutant full-length TNFα construct resistant to cleavage by TACE. Coculture of COS-7 cells expressing the mutant TNFα 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 mTNFα, establishing a feed-forward loop that may contribute to the establishment of chronic pain.
Zhou
Zhigang
Z
Department of Neurology, University of Michigan, USA VA Ann Arbor Healthcare System, Ann Arbor, MI 48109, USA.
Peng
Xiangmin
X
Hagshenas
Jafar
J
Insolera
Ryan
R
Fink
David J
DJ
Mata
Marina
M
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D019556:COS Cells / Q000502:physiology; D002450:Cell Communication / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; C099410:TAPI-2; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D013373:Substance P; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat