Retinal microglia initiate neuroinflammation in ocular autoimmunity

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.

Microglia and Inflammatory Responses in Diabetic Retinopathy

“…However, we prefer here using the broader pro-and anti-inflammatory nomenclature. Inflammation is principally an immune response meant to protect tissues from harm (8,34). When cell surface receptors detect damage-associated molecular patterns (DAMPs), microglia change their phenotype from a highly ramified form to an amoeboid shape with retracted processes and high motility (9).…”

“…In this state, microglia reactivity is not only triggered by DAMPs of retinal origin but also from the circulatory system (44). The recruitment of blood-derived monocytes to the retinal tissue is a highly coordinated process occurring through CCL2-CCR2 signaling (105) and involves resident microglia (34). These dysregulated immune responses in the retina increase production of cytokines and chemokines which damage the retinal vasculature and neurons and causes DME and PDR.…”

Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy

“…Microglia are the residential immune competent cells colonized in the central nervous system (CNS) and essential in maintaining the neuro-retinal homeostasis and innate immune defense mechanisms (4,5). Resting microglia typically present a highly ramified morphology (6) and contribute to retinal homeostasis by performing immune surveillance functions (7,8). Virtually, under all insults or disease conditions microglia become activated and undergo phenotypic and functional changes, which represents a fundamental innate immune mechanism to protect the retina from infection or injury.…”

Single Eye mRNA-Seq Reveals Normalisation of the Retinal Microglial Transcriptome Following Acute Inflammation

“…Microglia contribute to an immunosuppressive environment, are derived from the yolk-sac, reside within two distinct niches in the retina, and show differential regulation because of inherent microglial heterogeneity (7,8). Nonetheless conflicting data remains on how microglia regulate or promote inflammation depending on insult (9,10). During inflammation microglia alter their homeostatic state (8,(11)(12)(13).…”