The Immunomodulatory Role of Lipid Mediators in Experimental Autoimmune Uveitis

Title The Immunomodulatory Role of Lipid Mediators in Experimental Autoimmune Uveitis
Author, Co-Author Jessica Wei
Topic Treatment and Management of Posterior Sgmt Disease
Program Number
Ballroom A-B

Purpose: CD4 T cells differentiate into T helper subsets and T regulatory cells (Treg) to initiate or control adaptive immune responses. Aberrant T cell response during ocular inflammation can result in irreversible tissue damage that leads to blindness. We recently published that T effector function is controlled by lipoxin A4 (LXA4) in a dry eye model, demonstrated by LXA4 formation in the cervical draining lymph nodes. LXA4 is generated in tissues and mediates its effects by signaling through the GPCR ALX, which is expressed in T cells. We sought to understand how lipid mediators (LM) regulate immune response in experimental autoimmune uveitis (EAU) using mouse models that recapitulate key features of acute uveitis driven by autoreactive T cells.

Methods: LXA4 regulation of T cells was assessed using flow cytometry, polarization assay and proliferation assay. Unbiased metabolomics screening and q-PCR were used to identify endogenous LM candidates, compare levels of LM formation, and determine expression of biosynthetic enzymes and LM receptors in EAU. Uveitis pathology was assessed by histology and immunohistochemistry.

Results: Endogenous LXA4 levels are dramatically down regulated in the EAU lymph node compared to healthy and treated controls. T cell proliferation and T effector response are also inhibited after LXA4 treatment. In vivo, LXA4 treatment showed protective effects in EAU pathogenesis by preventing tissue damage, inflammation and cellular infiltration.

Conclusions: The findings demonstrate for the first time that immune regulatory LXA4 is formed in the retina and choroid and is a significant LM mediating the pathogenesis of autoimmune posterior uveitis.  In vitro and in vivo data demonstrate that the LXA4 circuit is protective and a key regulator of T cell driven uveitis. Emerging evidence demonstrates LXA4 regulation of adaptive immune responses and delineating the mechanism of action warrants further investigation.

Affiliation of Co-Authors