Abstract
Activated microglia exerts both beneficial and deleterious effects on neurons, but the signaling mechanism controlling these distinct responses remain unclear. We demonstrated that treatment of microglial cultures with the PAR-2 agonist, 2-Furoyl-LIGRLO-NH2, evoked early transient release of BDNF, while sustained PAR-2 stimulation evoked the delayed release of inflammatory cytokines (IL-1β and TNF-α) and nitric oxide. Culture medium harvested during the early phase (at 1 h) of microglial activation induced by 2-Furoyl-LIGRLO-NH2 (microglial conditioned medium, MCM) had no deleterious effects on cultured neurons, while MCM harvested during the late phase (at 72 h) promoted DNA fragmentation and apoptosis as indicated by TUNEL and annexin/PI staining. Blockade of PAR-1 during the early phase of PAR-2 stimulation enhanced BDNF release (by 11%, small but significant) while a PAR-1 agonist added during the late phase (24 h after 2-Furoyl-LIGRLO-NH2 addition) suppressed the release of cytokines and NO. The neuroprotective and neurotoxic effects of activated microglial exhibit distinct temporal profiles that are regulated by PAR-1 and PAR-2 stimulation. It may be possible to facilitate neuronal recovery and repair by appropriately timed stimulation and inhibition of microglial PAR-1 and PAR-2 receptors.
Highlights
Microglias are the major resident immunocompetent cells in the central nervous system (CNS)
Protease-activated receptors (PARs) are a unique family of four G protein-coupled receptors (PAR-1, -2, -3, and −4) [7]; PAR-1, PAR-3, and PAR-4 are activated by thrombin, whereas PAR-2 is activated by trypsin and tryptase [7]
Neuroprotective brain-derived neurotrophic factor (BDNF) was released from microglia during the early phase of the activation response while proinflammatory cytokines and cytotoxic nitric oxide (NO) were only released in response to sustained PAR-2 activation
Summary
Microglias are the major resident immunocompetent cells in the central nervous system (CNS). Activated microglia are part of an endogenous system promoting restoration of endangered CNS elements [2,3], while excessive and sustained stimulation of these cells contributes to neuropathology by causing the release of inflammatory mediators and neurotoxins [4,5,6]. Activation of microglial PAR-2 receptors promoted the secretion of neurotoxic factors like nitrite, reactive oxygen species (ROS), and TNF-α, and the conditioned media from microglia induced cell death in rat primary neuronal cultures [13,14]. It is known that activation of microglial PAR-2 promotes the expression of the ATP-gated ion channel P2X4R, which in turn can trigger the release of neuroprotective brain-derived neurotrophic factor (BDNF) [15,16,17]. Neurotrophic factors like BDNF mediate axon guidance during neural development and can enhance axonal growth following injury [18]
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