Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury
Izhar Livne-Bar, … , John G. Flanagan, Jeremy M. Sivak
Izhar Livne-Bar, … , John G. Flanagan, Jeremy M. Sivak
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4403-4414. https://doi.org/10.1172/JCI77398.
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 2

Astrocyte neuroprotection is mediated by a small secreted activity that is enriched in lipoxins.

Options: View larger image (or click on image) Download as PowerPoint
Astrocyte neuroprotection is mediated by a small secreted activity that ...
ACM or cell-free control media was injected intravitreally 1 day prior to KA challenge. (A) ACM treatment reduced KA-induced RGC loss compared with cell-free control media (RBPMS: green, arrows). (B) Quantification of RBPMS results showing significant RGC survival with ACM injection (n = 5). (C) Complimentary results showing ACM-mediated reduction in TUNEL-labeled cells (green, arrows) compared with control media. (D) Quantification of TUNEL results showing significant decrease in GCL apoptosis from ACM media (n = 5). (E) ACM protection was reproduced in vitro with HT22 neuronal cells challenged with 5 mM glutamate (n = 3). (F) Substantial protective activity in ACM is contained in a 3-kDa filtrate (n = 3). (G) High concentrations of LXA4 and LXB4 were detected in ACM compared with control media by LC-MS/MS (n = 3). Scale bar: 50 μm. *P < 0.05; **P < 0.01; ***P < 0.005. Bars represent SEM. Statistical analyses were performed by 1-way ANOVA with TUKEY post-hoc test.