Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation

Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A 4 and B 4 (LXA 4 and LXB 4 ) have protective activities against neurodegenerative injury. Yet, lipoxin activities and downstream signali...

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Bibliographic Details
Published in:Journal of neuroinflammation 2024-01, Vol.21 (1), p.1-18, Article 18
Main Authors: Livne-Bar, Izhar, Maurya, Shubham, Gronert, Karsten, Sivak, Jeremy M
Format: Article
Language:English
Subjects:
Analysis
Antibodies
Astrocytes
Care and treatment
Cell activation
Chemokine receptors
Chemokines
CXCL10 protein
CXCR3 protein
Cytokines
Diagnosis
Ganglion cells
Glia
Glial cells
Gliosis
Inflammation
Inflammation resolution
Lipids
Lipopolysaccharides
Lipoxin A4
Lipoxins
Microglia
Morphology
Mueller cells
Nervous system
Neurodegeneration
Neuroinflammation
Neuronal-glial interactions
Retina
Retinal diseases
Software
Uveitis
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Summary:Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A 4 and B 4 (LXA 4 and LXB 4 ) have protective activities against neurodegenerative injury. Yet, lipoxin activities and downstream signaling in neuroinflammatory processes are not well understood. Here, we utilized a model of posterior uveitis induced by lipopolysaccharide endotoxin (LPS), which results in rapid retinal neuroinflammation primarily characterized by activation of resident macroglia (astrocytes and Müller glia), and microglia. Using this model, we observed that each lipoxin reduces acute inner retinal inflammation by affecting endogenous glial responses in a cascading sequence beginning with astrocytes and then microglia, depending on the timing of exposure; prophylactic or therapeutic. Subsequent analyses of retinal cytokines and chemokines revealed inhibition of both CXCL9 (MIG) and CXCL10 (IP10) by each lipoxin, compared to controls, following LPS injection. CXCL9 and CXCL10 are common ligands for the CXCR3 chemokine receptor, which is prominently expressed in inner retinal astrocytes and ganglion cells. We found that CXCR3 inhibition reduces LPS-induced neuroinflammation, while CXCR3 agonism alone induces astrocyte reactivity. Together, these data uncover a novel lipoxin–CXCR3 pathway to promote distinct anti-inflammatory and proresolution cascades in endogenous retinal glia.
ISSN:1742-2094
1742-2094
DOI:10.1186/s12974-024-03010-0