Neuroprotection through pharmacological targeting retinal immune microenvironment in retinal neurodegenerative diseases

Abstract

Neurodegeneration is a complex process involving the structural and functional loss of neurons and ultimately cell death. Retinal neurodegeneration occurs in glaucoma, retinal ischemia and many other ocular diseases, leading to severe vision impairment and even blindness. Neuroinflammation is increasingly reported as a key driver in the progression of neurodegeneration. As the first line of defending immune cells in the retina, microglial cells play a critical role in the surveillance of surroundings and can make rapid responses to any disturbances to protect neurons from pathogens or infections. However, prolonged microglial activation can lead to neurotoxicity and cell death. Current available treatment options for neurodegenerative diseases are very limited. Emerging evidence suggests that suppression of neuroinflammation may present a potential therapy for these diseases. In our studies, we identified through in-depth RNA-sequencing and single-cell RNA sequencing analyses that insulin-like growth factor binding protein like protein 1 (IGFBPL1) is a key regulator of pro-homeostatic microglia. IGFBPL1 exerted remarkably potent therapeutic effects by inhibiting neuroinflammation and/or microglial activation in vitro and in vivo via IGF-1R signaling and supported neuronal survival in different mouse models of glaucoma. It promoted physiological and visual function recovery as demonstrated by electroretinogram (ERG) and optomotor response (OMR)-based visual behavior assays. In addition, we found that baicalein (5,6,7­trihydroxyflavone; C15H10O5), a natural flavonoid extracted from the root of Scutellaria baocalensis Georgi (SB), effectively suppressed the activation of LPS-primed human and mouse microglial cells via inhibiting pho-PI3K/NFkB axis. Further proteomic study indicated such inhibitory roles of baicalein on the IL-17 pathway and upstream regulators of IL-1β and TLR4, which was subsequently supported by in vivo results using retinal ischemia/reperfusion (I/R) mouse model. Therapeutic administration of baicalein not only suppressed microglia­dependent inflammatory cascades and also exhibited neuroprotective effects and improved visual functions post-retinal I/R injury. These results provide new promising alternatives for treating retinal neurodegenerative diseases via suppression of neuroinflammation.