title: Copper modulates the phenotypic response of activated BV2 microglia through the release of nitric oxide.
abstract: Microglia are resident immune cells of the central nervous system. Their persistent activation in neurodegenerative diseases, traditionally attributed to neuronal dysfunction, may be due to a microglial failure to modulate the release of cytotoxic mediators such as nitric oxide (NO). The persistent activation of microglia with the subsequent release of NO vis-á-vis the accumulation of redox transition metals such as copper (Cu) in neurodegenerative diseases, prompted the hypothesis that copper would alter NO signaling by changing the redox environment of the cell and that, by altering the fate of NO, microglia would adopt a different phenotype. We have used the microglial cell model, BV2, to examine the effects of Cu(I) on NO production and activation as they have been shown to be phenotypically plastic. Our results show that cell viability is not affected by Cu(I) in BV2 microglia and that it has no effect on iNOS mRNA, protein expression and nitrite release. However, when LPS is added to Cu(I)-treated medium, nitrite release is abrogated while iNOS expression is not significantly altered. This effect is Cu(I)-specific and it is not observed with other non-redox metals, suggesting that Cu(I) modulates NO reactivity. Immunofluorescence analysis shows that the M1 (inflammatory) phenotype of BV2 microglia observed in response to LPS, is shifted to an M2 (adaptive) phenotype when Cu(I) is administered in combination with LPS. This same shift is not observed when iNOS function is inhibited by 1400W. In the present study we show that Cu(I) modulates the release of NO to the media, without altering iNOS expression, and produces phenotypic changes in BV2 microglia.
authors: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA. Electr albarg@rci.rutgers.edu
authors: Alba
authors: A
authors: Rossi-George
authors: Chang-Jiang
authors: CJ
authors: Guo
authors: Benjamin L
authors: BL
authors: Oakes
authors: Andrew J
authors: AJ
authors: Gow
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003300:Copper / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010641:Phenotype
chemical_list: D018836:Inflammation Mediators; D009569:Nitric Oxide; D003300:Copper