Retinal microglia initiate neuroinflammation in ocular autoimmunity

Significance

Autoimmune uveitis is a serious sight-threatening condition defined by an autoreactive immune response against uveal tissues and the retina. As a result, patients with uveitis often suffer serious visual loss after persistent inflammation due to immune-mediated damage in the targeted tissues. Microglia are resident immune cells in the retina, and are thought to be the key population that initiates retinal inflammation; however, the exact role for microglia in autoimmune uveitis is still unknown. Here, we demonstrate that microglia are essential for the induction of a retinal autoimmune response, as microglial ablation completely blocks disease. Our data suggest that microglia mediate autoreactive immune cell entry into the retina, and that by depleting microglia, circulating immune cells cannot gain entry into the retina.

Abstract

Autoimmune uveitis is a sight-threatening ocular inflammatory condition in which the retina and uveal tissues become a target of autoreactive immune cells. While microglia have been studied extensively in autoimmune uveitis, their exact function remains uncertain. The objective of the current study was to determine whether resident microglia are necessary and sufficient to initiate and amplify retinal inflammation in autoimmune uveitis. In this study, we clearly demonstrate that microglia are essential for initiating infiltration of immune cells utilizing a murine model of experimental autoimmune uveoretinitis (EAU) and the recently identified microglia-specific marker P2ry12. Initiating disease is the primary function of microglia in EAU, since eliminating microglia during the later stages of EAU had little effect, indicating that the function of circulating leukocytes is to amplify and sustain destructive inflammation once microglia have triggered disease. In the absence of microglia, uveitis does not develop, since leukocytes cannot gain entry through the blood-retinal barrier, illustrating that microglia play a critical role in regulating infiltration of inflammatory cells into the retina.