Disrupting the CD47/SIRPα Axis Protects Against Traumatic Optic Neuropathy

Traumatic optic neuropathy (TON) is a serious injury to the optic nerve that can lead to vision impairment or blindness. Current treatment options include corticosteroids or surgical decompression. There is no consensus on the treatment of TON due to insufficient evidence supporting the effectiveness of current options. Cluster of differentiation 47 (CD47) is a transmembrane protein that can be upregulated on apoptotic cells. It prevents their phagocytic clearance or efferocytosis by communicating a “don’t eat me” signal when it binds to signal regulatory protein α (SIRPα) on myeloid cells. We found that CD47 is upregulated in the retina after the optic nerve crush (ONC) injury model of TON, along with the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Antibody neutralization of TNF-α after ONC resulted in blunted CD47 levels whereas treating ex-vivo retinal explants with recombinant TNF-α resulted in increased levels of CD47, indicating that TNF-α stimulates CD47 expression. To investigate the therapeutic potential of blocking the CD47/SIRPα axis after ONC, we intravitreally treated WT mice with anti-CD47, anti-SIRPα, or anti-IgG (control) post-ONC injury. Anti-CD47 treatments resulted in improved efferocytosis, attenuated neurodegeneration, improved retinal thickness, and enhanced retinal function as compared to anti-IgG control treatment post-ONC. Conversely, anti-SIRPα did not show statistically significant neuronal preservation after ONC. Myeloid-specific SIRPα deletion reduced retinal thinning and only showed a neuroprotective trend for retinal ganglion cell count and function after ONC. Collectively, our data indicate that the CD47-SIRPα axis is a promising therapeutic target to improve retinal outcomes following ONC injury, with CD47 neutralization proving more effective than targeting SIRPα.