Alpha retinal ganglion cell-derived SPP1 instructs microglia to limit neurodegeneration

Communication between neurons and microglia is essential for microglial functions and neuronal survival. Here we report that alpha retinal ganglion cells (αRGCs) respond to glaucomatous or traumatic axonal injury by increasing the expression and secretion of secreted phosphoprotein 1 (SPP1), which in turn instructs retinal microglia to assume a neuroprotective phenotype. Alpha RGCs increase the secretion of SPP1, which acts on its specific receptor, ItgαV, on microglia and elicits transcriptional and morphological changes. SPP1 functionally increases the capacity of microglia to clear protein aggregates and inhibits neuroinflammation. SPP1 positively regulates microglial debris clearance through an upregulation of autophagy-selective receptors. This shifts microglia towards the expression of neuroprotective mediators, such as interleukin-10, protecting ganglion cells and limiting vision decline. Our findings identify SPP1 as a key mediator of αRGC-microglia crosstalk in autophagy and debris clearance, and a promising candidate for therapy in neurodegeneration.