Attenuated adenosine mediated immune-dampening increases natural killer cell activity in early age-related macular degeneration

Abstract

Non-exudative age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) dysfunction and has been linked to altered intraocular immunity. Our investigation focuses on immune cell subsets and inflammation-associated factors in the eyes with early and intermediate AMD. We observed elevated levels of activated natural killer (NK) cells and interferon-{gamma}, concurrent with reduced myeloid-derived suppressor cells (MDSCs) and adenosine in AMD eyes. Aqueous humor from AMD patients had diminished ability to dampen NK cell activation, an effect rescued by adenosine supplementation. The Cryba1 cKO mouse model recapitulated these immune alterations, and single-cell RNA-sequencing identified NK cell-related genes and NK cell-RPE interactions. Co-culture of activated NK cells with RPE cells induced barrier dysfunction and Gasdermin-E driven pyroptosis providing a functional link relevant to AMD. These findings suggest a double-hit model where elevated immune activation and loss of immune dampening mechanisms drive AMD progression. Resetting the intraocular immune balance may be a promising therapeutic strategy for managing early and intermediate AMD. O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/634301v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1516bfaorg.highwire.dtl.DTLVardef@87f505org.highwire.dtl.DTLVardef@1e725caorg.highwire.dtl.DTLVardef@622717_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Illustra tion of pro posed mechanism underlying NK cell-RPE interaction in early AMD pathogenesis. Dysregulated NK cell communicate s with stressed RPE in early AMD immunopathology. Aberrant AMD aqueous humor and retina shows increased NK cells and NK effector molecules like IFN{gamma} with reduced MDSC and adenosine in human subjects, don or eye and animal model. Activated NK cells interaction with RPE causes dysfunction and pyroptotic cell death via Gasdermin-E pathway in AMD.. Created with BioRender.com C_FIG