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
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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

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Figure 4

LXA4 and LXB4 promote RGC survival following acute injury.

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LXA4 and LXB4 promote RGC survival following acute injury. (A) Intravitr...
(A) Intravitreal injection of 10 μM LXA4 or LXB4 prior to KA-induced insult resulted in increased RGC survival compared with control (PBS) (RBPMS: green, arrows). (B) Corresponding quantification shows significant increases in RGC survival with LXA4 or LXB4 treatment compared with vehicle control. Values are presented as fold change from noninjured controls (n = 8). (C and D) In contrast, intravitreal treatment with 10 μM of the 5-LOX inhibitor zileuton significantly compromised RGC survival following acute stress compared with vehicle (n = 5). (E and F) Similarly, 15 μM of the ALX/FPR2 inhibitor WRW4 significantly reduced RGC survival following acute stress compared with vehicle (n = 5). Scale bar: 50 μm. *P < 0.05. Bars represent SEM. Statistical analyses were performed by 1-way ANOVA with TUKEY post-hoc test.