Abstract
Purpose :
To establish whether the small lipid mediators LXA4 and LXB4 (lipoxins) affect retinal neuroinflammation in a model of posterior uveitis induced by lipopolysaccharide endotoxin (LPS), and to investigate lipoxin modes of action in mediating retinal inflammation.
Methods :
Acute posterior uveitis was induced by intravitreal injection of LPS (150ng). LXA4, LXB4 or vehicle control were also delivered by intravitreal injection at select time points prior to or following LPS challenge. Retinas were fixed and processed for immunofluorescent detection of endogenous and infiltrating inflammation markers. In order to measure retinal levels of cytokines and chemokines, eyes were collected 24 hrs post injections and retinas were homogenized and snap frozen. Samples were then submitted to quantitative multiplex laser bead analyses.
Results :
We found that intravitreal LPS induced rapid neuroinflammation primarily characterized by activation of retinal macroglia (astrocytes and Müller glia), and microglia. Using this model, we observed that each of the two lipoxins reduced acute inner retinal inflammation in distinct ways, depending on prophylactic or therapeutic exposure. Analyses of inflammation-associated retinal cytokines and chemokines, revealed reduction of CXCL9 (MIG) and CXCL10 (IP10) by either lipoxin in comparison to control. Interestingly, both CXCL9 and CXCL10 are ligands activating the CXCR3 chemokine receptor which is abundantly expressed in the inner retina. We found that CXCR3 inhibition reduces LPS-induced inflammation, while CXCR3 agonism alone induces retinal-glia reactivity.
Conclusions :
These findings indicate that the lipoxins promote distinct anti-inflammatory and pro-resolution actions in endogenous retinal glia, in part via the CXCR3 chemokine receptor.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.