Inflammatory responses by retinal astrocytes during pathogenesis of normal-tension glaucoma

Abstract

Glaucoma is the first cause of blindness in Japan, which is characterized by progressive degeneration of retinal ganglion cells (RGCs). Although an elevated intraocular pressure (IOP) is one of major risk factors, many Japanese glaucoma patients show normal level of IOP (i.e. normal tension glaucoma, NTG). We have recently discovered a novel NTG model (Astro-KO) mouse in which astrocytes lack the gene encoding ATP-binding cassette transporter A1 (ABCA1). The NTG mice at 3 months old (mo) showed no RGC damages but showed significant damages of RGCs and visual impairment at 12 mo. Although dysfunction of astrocytes was essential for NTG-like pathologies, molecular mechanisms remained unclear. To tackle this, we performed bulk and single-cell RNA-sequence of retina. We found that RGCs and retinal astrocytes up-regulate neuroinflammatory pathways including CXCR4 and CCR5 signaling. Immuonhistochemical analysis revealed that CXCL12 and CCL5, ligands for CXCR4 and CCR5, were up-regulated in retinal astrocytes of Astro-KO mice at 12 mo. CXCR4 and CCR5 in Astro-KO mice (12 mo) were expressed in the ganglion cell layer. Taken together, our data showed that lack of ABCA1 triggers neuroinflammation by astrocytes, which may cause RGC damages via CXCR4 and CCR5 activation.