A novel role for lipoxin A₄ in driving a lymph node-eye axis that controls autoimmunity to the neuroretina

The eicosanoid lipoxin A₄ (LXA₄) has emerging roles in lymphocyte-driven diseases. We identified reduced LXA₄ levels in posterior segment uveitis patients and investigated the role of LXA₄ in the pathogenesis of experimental autoimmune uveitis (EAU). Immunization for EAU with a retinal self-antigen caused selective downregulation of LXA₄ in lymph nodes draining the site of immunization, while at the same time amplifying LXA₄ in the inflamed target tissue. T cell effector function, migration and glycolytic responses were amplified in LXA₄-deficient mice, which correlated with more severe pathology, whereas LXA₄ treatment attenuated disease. In vivo deletion or supplementation of LXA₄ identified modulation of CC-chemokine receptor 7 (CCR7) and sphingosine 1- phosphate receptor-1 (S1PR1) expression and glucose metabolism in CD4⁺ T cells as potential mechanisms for LXA₄ regulation of T cell effector function and trafficking. Our results demonstrate the intrinsic lymph node LXA₄ pathway as a significant checkpoint in the development and severity of adaptive immunity.