Transient early neurotrophin release and delayed inflammatory cytokine release by microglia in response to PAR-2 stimulation.
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-1 β 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.
Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. 1002153376@qq.com.
Chen-Wen
CW
Chen
Qian-Bo
QB
Chen
Qing
Q
Ouyang
Ji-Hu
JH
Sun
Fang-Ting
FT
Liu
Dian-Wen
DW
Song
Hong-Bin
HB
Yuan
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000276:immunology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000502:physiology*; D013997:Time Factors
C487404:2-furoyl-LIGRLO-amide; D016207:Cytokines; D018836:Inflammation Mediators; D009414:Nerve Growth Factors; D009842:Oligopeptides; D044464:Receptor, PAR-2