A novel role for lipoxin A(4) in driving a lymph node–eye axis that controls autoimmunity to the neuroretina

The eicosanoid lipoxin A(4) (LXA(4)) has emerging roles in lymphocyte-driven diseases. We identified reduced LXA(4) levels in posterior segment uveitis patients and investigated the role of LXA(4) in the pathogenesis of experimental autoimmune uveitis (EAU). Immunization for EAU with a retinal self-antigen caused selective downregulation of LXA(4) in lymph nodes draining the site of immunization, while at the same time amplifying LXA(4) in the inflamed target tissue. T cell effector function, migration and glycolytic responses were amplified in LXA(4)-deficient mice, which correlated with more severe pathology, whereas LXA(4) treatment attenuated disease. In vivo deletion or supplementation of LXA(4) 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 LXA(4) regulation of T cell effector function and trafficking. Our results demonstrate the intrinsic lymph node LXA(4) pathway as a significant checkpoint in the development and severity of adaptive immunity.