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

摘要

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