TY - JOUR
T1 - FGF-1 triggers pannexin-1 hemichannel opening in spinal astrocytes of rodents and promotes inflammatory responses in acute spinal cord slices
AU - Garré, Juan Mauricio
AU - Yang, Guang
AU - Bukauskas, Feliksas F.
AU - Bennett, Michael V.L.
N1 - Publisher Copyright:
© 2016 the authors.
PY - 2016/4/27
Y1 - 2016/4/27
N2 - We show here that the growth factor FGF-1 is proinflammatory in the spinal cord and explore the inflammatory mechanisms. FGF-1 applied to rat spinal astrocytes in culture initiates calcium signaling and induces secretion of ATP that within minutes increases membrane permeability to ethidium (Etd+) and Ca2+by activatingP2X7 receptors (P2X7Rs) that open pannexin hemichannels (Px1 HCs) that release further ATP; by 7 h treatment, connexin 43 hemichannels (Cx43 HCs) are also opened. In acute mouse spinal cord slices ex vivo, we found that FGF-1 treatment for 1 h increases the percentage of GFAP-positive astrocytes that show enhanced Px1 HC-mediated Etd+ uptake. This response to FGF-1 was not observed in astrocytes in slices of cerebral cortex. FGF-1-induced dye uptake by astrocytes is prevented byBAPTA-AMor a phospholipaseC(PLC) inhibitor. Furthermore, in spinal cord slices,P2X7Rantagonists (BBG and A740003) and Px1HCblockers (10Panx1 and carbenoxolone) prevent the increase in Etd+uptake by astrocytes, whereas Gap19, a selective Cx43HC blocker, has no effect on dye uptake at this time. Microglia are not required for the increase in Etd+ uptake by astrocytes induced by FGF-1, although they are activated by FGF-1 treatment. The morphological signs of microglia activation are inhibited by P2X7R antagonists and 10Panx1 and are associated with elevated levels of proinflammatory cytokines in cord slices treated with FGF-1. The FGF-1 initiated cascade may play an important role in spinal cord inflammation in vivo.
AB - We show here that the growth factor FGF-1 is proinflammatory in the spinal cord and explore the inflammatory mechanisms. FGF-1 applied to rat spinal astrocytes in culture initiates calcium signaling and induces secretion of ATP that within minutes increases membrane permeability to ethidium (Etd+) and Ca2+by activatingP2X7 receptors (P2X7Rs) that open pannexin hemichannels (Px1 HCs) that release further ATP; by 7 h treatment, connexin 43 hemichannels (Cx43 HCs) are also opened. In acute mouse spinal cord slices ex vivo, we found that FGF-1 treatment for 1 h increases the percentage of GFAP-positive astrocytes that show enhanced Px1 HC-mediated Etd+ uptake. This response to FGF-1 was not observed in astrocytes in slices of cerebral cortex. FGF-1-induced dye uptake by astrocytes is prevented byBAPTA-AMor a phospholipaseC(PLC) inhibitor. Furthermore, in spinal cord slices,P2X7Rantagonists (BBG and A740003) and Px1HCblockers (10Panx1 and carbenoxolone) prevent the increase in Etd+uptake by astrocytes, whereas Gap19, a selective Cx43HC blocker, has no effect on dye uptake at this time. Microglia are not required for the increase in Etd+ uptake by astrocytes induced by FGF-1, although they are activated by FGF-1 treatment. The morphological signs of microglia activation are inhibited by P2X7R antagonists and 10Panx1 and are associated with elevated levels of proinflammatory cytokines in cord slices treated with FGF-1. The FGF-1 initiated cascade may play an important role in spinal cord inflammation in vivo.
KW - Astrocyte
KW - Fibroblast growth factor
KW - Glia
KW - Inflammation
KW - Microglia
KW - Spinal cord
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U2 - 10.1523/JNEUROSCI.4195-15.2016
DO - 10.1523/JNEUROSCI.4195-15.2016
M3 - Article
C2 - 27122036
AN - SCOPUS:84966546697
SN - 0270-6474
VL - 36
SP - 4785
EP - 4801
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -