title: beta2 Adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway.
abstract: Activation of the beta2 adrenergic receptor (beta2AR) on immune cells has been reported to possess anti-inflammatory properties, however, the pro-inflammatory properties of beta2AR activation remain unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that salmeterol, a long-acting beta2AR agonist, selectively induces dopaminergic (DA) neurotoxicity through its ability to activate microglia. Salmeterol selectively increased the production of reactive oxygen species (ROS) by NADPH oxidase (PHOX), the major superoxide-producing enzyme in microglia. A key role of PHOX in mediating salmeterol-induced neurotoxicity was demonstrated by the inhibition of DA neurotoxicity in cultures pretreated with diphenylene-iodonium (DPI), an inhibitor of PHOX activity. Mechanistic studies revealed the activation of microglia by salmeterol results in the selective phosphorylation of ERK, a signaling pathway required for the translocation of the PHOX cytosolic subunit p47(phox) to the cell membrane. Furthermore, we found ERK inhibition, but not protein kinase A (PKA) inhibition, significantly abolished salmeterol-induced superoxide production, p47(phox) translocation, and its ability to mediate neurotoxicity. Together, these findings indicate that beta2AR activation induces microglial PHOX activation and DA neurotoxicity through an ERK-dependent/PKA-independent pathway.
authors.affiliation: Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, North Carolina 27599-7455, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Amanda
authors.initials: A
authors.lastname: Snyder
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Wu
authors.forename: Yachen
authors.initials: Y
authors.lastname: Li
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Flood