Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation
Abstract Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) have protective activities against neurodegenerative injury. Yet, lipoxin activities and downstream sig...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-024-03010-0 |
| _version_ | 1797355649397424128 |
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| author | Izhar Livne-Bar Shubham Maurya Karsten Gronert Jeremy M. Sivak |
| author_facet | Izhar Livne-Bar Shubham Maurya Karsten Gronert Jeremy M. Sivak |
| author_sort | Izhar Livne-Bar |
| collection | DOAJ |
| description | Abstract Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) 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. |
| first_indexed | 2024-03-08T14:14:11Z |
| format | Article |
| id | doaj.art-6dbf4018fefc4d41be13e85194369231 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-08T14:14:11Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-6dbf4018fefc4d41be13e851943692312024-01-14T12:30:45ZengBMCJournal of Neuroinflammation1742-20942024-01-0121111310.1186/s12974-024-03010-0Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammationIzhar Livne-Bar0Shubham Maurya1Karsten Gronert2Jeremy M. Sivak3Department of Vision Sciences, Donald K Johnson Eye Institute, Krembil Research Institute, University Health NetworkHerbert Wertheim School of Optometry and Vision Science, University of California BerkeleyHerbert Wertheim School of Optometry and Vision Science, University of California BerkeleyDepartment of Vision Sciences, Donald K Johnson Eye Institute, Krembil Research Institute, University Health NetworkAbstract Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) 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.https://doi.org/10.1186/s12974-024-03010-0LipoxinsRetinaUveitisNeuroinflammationInflammation resolutionGliosis |
| spellingShingle | Izhar Livne-Bar Shubham Maurya Karsten Gronert Jeremy M. Sivak Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation Journal of Neuroinflammation Lipoxins Retina Uveitis Neuroinflammation Inflammation resolution Gliosis |
| title | Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation |
| title_full | Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation |
| title_fullStr | Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation |
| title_full_unstemmed | Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation |
| title_short | Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation |
| title_sort | lipoxins a4 and b4 inhibit glial cell activation via cxcr3 signaling in acute retinal neuroinflammation |
| topic | Lipoxins Retina Uveitis Neuroinflammation Inflammation resolution Gliosis |
| url | https://doi.org/10.1186/s12974-024-03010-0 |
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