Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury
Izhar Livne-Bar, Jessica Wei, Hsin-Hua Liu, Samih Alqawlaq, Gah-Jone Won, Alessandra Tuccitto, Karsten Gronert, John G. Flanagan, Jeremy M. Sivak
Izhar Livne-Bar, Jessica Wei, Hsin-Hua Liu, Samih Alqawlaq, Gah-Jone Won, Alessandra Tuccitto, Karsten Gronert, John G. Flanagan, Jeremy M. Sivak
View: Text | PDF
Research Article Cell biology Neuroscience Ophthalmology

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Abstract

Astrocytes perform critical non–cell autonomous roles following CNS injury that involve either neurotoxic or neuroprotective effects. Yet the nature of potential prosurvival cues has remained unclear. In the current study, we utilized the close interaction between astrocytes and retinal ganglion cells (RGCs) in the eye to characterize a secreted neuroprotective signal present in retinal astrocyte conditioned medium (ACM). Rather than a conventional peptide neurotrophic factor, we identified a prominent lipid component of the neuroprotective signal through metabolomics screening. The lipoxins LXA4 and LXB4 are small lipid mediators that act locally to dampen inflammation, but they have not been linked directly to neuronal actions. Here, we determined that LXA4 and LXB4 are synthesized in the inner retina, but their levels are reduced following injury. Injection of either lipoxin was sufficient for neuroprotection following acute injury, while inhibition of key lipoxin pathway components exacerbated injury-induced damage. Although LXA4 signaling has been extensively investigated, LXB4, the less studied lipoxin, emerged to be more potent in protection. Moreover, LXB4 neuroprotection was different from that of established LXA4 signaling, and therapeutic LXB4 treatment was efficacious in a chronic model of the common neurodegenerative disease glaucoma. Together, these results identify a potential paracrine mechanism that coordinates neuronal homeostasis and inflammation in the CNS.

Authors

Izhar Livne-Bar, Jessica Wei, Hsin-Hua Liu, Samih Alqawlaq, Gah-Jone Won, Alessandra Tuccitto, Karsten Gronert, John G. Flanagan, Jeremy M. Sivak

×

Figure 3

Lipoxins are regulated in the inner retina in response to acute injury.

Options: View larger image (or click on image) Download as PowerPoint
Lipoxins are regulated in the inner retina in response to acute injury. ...
(A) qPCR of mouse retinal cDNAs shows significantly reduced expression of Alox5 and Fpr2, but not Alox15, 2 hours after KA insult compared with PBS controls (n = 3). (B) LXB4 concentrations in total mouse retina are reduced at 6 hours following injury, while LXA4 concentrations are reduced in the ON compared with PBS-injected controls (n = 10 retinas/aggregate group). (C) Confocal microscopy shows 5-LOX immunostaining in primary RAs. (D) Confocal imaging of 5-LOX immunostaining (green) shows accumulation in the GCL and NFL, with partial colocalization (yellow, arrows) in astrocytes (GFAP: red). (E) Signal for 5-LOX in the inner retina is reduced at 3 and 6 hours after injury (arrows). (F) FPR2 immunostaining (green) is prominent in cultured primary RGCs stained with β3-tubulin (red). (G) ALX/FPR2 immunostaining (green) is specific to the GCL and colocalizes (yellow, arrows) with RGCs (Brn3a: red). Scale bars: 20 μm (C and F); 10 μm (D and G). ***P < 0.005. Bars represent SEM. Statistical analyses were performed by 1-way ANOVA with TUKEY post-hoc test.