Intraocular CD47 blockade modulates the immune response in autoimmune uveitis

Non-infectious uveitis is a sight-threatening intraocular inflammatory disease, often driven by autoimmune responses, with limited treatment options and significant adverse effects associated with long-term immunosuppression. CD47, known for driving a tonic inhibitory signal that suppresses macrophage activity via SIRPα, has emerged as a potential immunomodulatory target, yet its cell-specific and tissue-dependent functions in autoimmune uveitis remain poorly understood. Using an adoptive transfer model that circumvents peripheral T cell activation, we explored the role of CD47 during the effector phase of experimental autoimmune uveitis (EAU), focusing specifically on retinal inflammation driven by peripheral myeloid cells (PM) and microglia. CD47-deficiency reduced disease severity, revealing a PM- and microglia- mediated mechanism that extends beyond the prevailing notion that in autoimmune neuroinflammation CD47 acts mainly through systemic T-cell modulation. Transcriptomic profiling showed that CD47 loss reshapes signaling pathways in infiltrating PMs and skews microglia toward a protective, non-inflammatory state including upregulation of the inhibitory receptor SIRPα. Consistent with a protective role for SIRPα, intravitreal anti-SIRPα treatment worsened the pathology. Notably, systemic anti-CD47 administration exacerbated disease severity, whereas local intravitreal delivery markedly suppressed it. Single-cell RNA sequencing of retinal myeloid cells further showed that intraocular CD47 blockade suppresses interferon-stimulated genes, induces immediate-early/AP-1 responses and modulates tissue-remodeling gene programs, shifting both microglia and infiltrating PMs toward a less inflammatory, pro-resolving state. Together, these findings support the potential of targeting CD47 locally as an effective strategy to restrain pathogenic myeloid responses in autoimmune uveitis while preserving systemic immunity.