The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment

• Published in: Journal of neuroinflammation Vol. 21; no. 1; p. 74
• Main Authors: Abcouwer, Steven F, Miglioranza Scavuzzi, Bruna, Kish, Phillip E, Kong, Dejuan, Shanmugam, Sumathi, Le, Xuan An, Yao, Jingyu, Hager, Heather, Zacks, David N
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 25.03.2024; BioMed Central; BMC
• Subjects: Age; Animals; Bone Morphogenetic Protein Receptors - metabolism; Chemokines; Complications and side effects; Connexin 43; Development and progression; Down-regulation; Epithelium; Gap junctions; Gene expression; Genes; Genetic aspects; Genomes; Health aspects; Humans; Hyaluronic acid; Immune response; Immune system; Inflammation; Innate immunity; Kinases; Laboratories; Lipocalin; Macular degeneration; Macular Degeneration - metabolism; Messenger RNA; Metabolites; Mice; Phagocytosis; Phagocytosis - genetics; Photopigments; Pigmentation; Proteasomes; Proteins; Proteolysis; Retina; Retina - metabolism; Retinal detachment; Retinal Detachment - metabolism; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; RNA sequencing; Tight junctions; Transcriptomes; Visual perception; United States
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-024-03062-2

The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, and forms the outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic retinal dystrophies and contributes to age-related macular degeneration. Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers. Although the retinal response to RD is highly studied, little is known about how the RPE responds to loss of this interaction. RNA sequencing (RNA-Seq) was used to compare normal and detached RPE in the C57BL6/J mouse. The naïve mouse RPE transcriptome was compared to previously published RPE signature gene lists and from the union of these 14 genes (Bmp4, Crim1, Degs1, Gja1, Itgav, Mfap3l, Pdpn, Ptgds, Rbp1, Rnf13, Rpe65, Slc4a2, Sulf1 and Ttr) representing a core signature gene set applicable across rodent and human RPE was derived. Gene ontology enrichment analysis (GOEA) of the mouse RPE transcriptome identified expected RPE features and functions, such as pigmentation, phagocytosis, lysosomal and proteasomal degradation of proteins, and barrier function. Differentially expressed genes (DEG) at 1 and 7 days post retinal detachment (dprd) were defined as mRNA with a significant (p ≤0.05) fold change (FC) of 0.67 ≥ FC ≥ 1.5 in detached versus naïve RPE. The RPE transcriptome exhibited dramatic changes at 1 dprd, with 2297 DEG identified. The KEGG pathways and biological process GO groups related to innate immune responses were significantly enriched. Lipocalin 2 (Lcn2) and several chemokines were upregulated, while numerous genes related to RPE functions, such as pigment synthesis, visual cycle, phagocytosis, and tight junctions were downregulated at 1 dprd. The response was largely transient, with only 18 significant DEG identified at 7 dprd, including upregulation of complement gene C4b. Validation studies confirmed RNA-Seq results. Thus, the RPE quickly downregulates cell-specific functions and mounts an innate immune defense response following RD. Our data demonstrate that the RPE contributes to the inflammatory response to RD and may play a role in attraction of immune cells to the subretinal space.