ABSTRACT
Injuries to the retinal pigment epithelium (RPE) trigger immune responses, orchestrating interactions within the innate and adaptive immune systems in the outer retina and choroid. We previously reported that interleukin 17 (IL-17) is a pivotal signaling molecule originating from choroidal γδ T cells, exerting protective effects by mediating functional connections between the RPE and subretinal microglia. In this current study, we generated mice with aryl hydrocarbon receptor (AhR) knockout specifically in IL-17-producing cells. These animals had deficiency in IL-17 production from γδ T cells, and exhibited increased sensitivity to both acute and chronic insults targeting the RPE. These findings imply that IL-17 plays a crucial role as a signaling cytokine in preserving the homeostasis of the outer retina and choroid.
Subject(s)
Interleukin-17 , Receptors, Aryl Hydrocarbon , Retinal Pigment Epithelium , Animals , Mice , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/immunology , Basic Helix-Loop-Helix Transcription Factors/genetics , Choroid/immunology , Choroid/pathology , Choroid/metabolism , Interleukin-17/metabolism , Interleukin-17/immunology , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Mice, Inbred C57BL , Mice, Knockout , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Aryl Hydrocarbon/immunology , Receptors, Aryl Hydrocarbon/genetics , Retinal Degeneration/immunology , Retinal Degeneration/pathology , Retinal Degeneration/metabolism , Retinal Pigment Epithelium/immunology , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Signal Transduction/immunologyABSTRACT
Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal γδ T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to characterize the profiles of immune cells in mouse choroid. We found that γδ T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor on the RPE, subsequently triggering the production of interleukin-6. This cascade of cytokines initiated a metabolic reprogramming of subretinal microglia, enhancing their capacity for lipid metabolism. RPE-specific knockout of IL-17 receptor A led to the dysfunction of subretinal microglia and RPE pathology. Collectively, our findings suggest that responding to RPE injury, the choroidal γδ T cells can initiate a protective signaling cascade that ensures the proper functioning of subretinal microglia.
Subject(s)
Macular Degeneration , Retinal Degeneration , Animals , Mice , Cytokines/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Macular Degeneration/pathology , Retina/metabolism , Retinal Degeneration/metabolism , Retinal Pigment Epithelium/metabolismABSTRACT
The retinal pigment epithelium (RPE), the outermost layer of the retina, provides essential support to both the neural retina and choroid. Additionally, the RPE is highly active in modulating functions of immune cells such as microglia, which migrate to the subretinal compartment during aging and age-related degeneration. Recently, studies have highlighted the important roles of microRNA (miRNA) in the coordination of general tissue maintenance as well as in chronic inflammatory conditions. In this study, we analyzed the miRNA profiles in extracellular vesicles (EVs) released by the RPE, and identified and validated miRNA species whose expression levels showed age-dependent changes in the EVs. Using co-culture of RPE and retinal microglia, we further demonstrated that miR-21 was transferred between the two types of cells, and the increased miR-21 in microglia influenced the expression of genes downstream of the p53 pathway. These findings suggest that exosome-mediated miRNA transfer is a signaling mechanism that contributes to the regulation of microglia function in the aging retina.