Hematogenous Macrophages Contribute to Fibrotic Scar Formation After Optic Nerve Crush

Although glial scar formation has been extensively studied after optic nerve injury, the existence and characteristics of traumatic optic nerve fibrotic scar formation have not been previously characterized. Recent evidence suggests infiltrating macrophages are involved in pathological processes after optic nerve crush (ONC), but their role in fibrotic scar formation is unknown. Using wild-type and transgenic mouse models with optic nerve crush injury, we show that macrophages infiltrate and associate with fibroblasts in the traumatic optic nerve lesion fibrotic scar. We dissected the role of hematogenous and resident macrophages, labeled with Dil liposomes intravenously administered, and observed that hematogenous macrophages (Dil⁺ cells) specifically accumulate in the center of traumatic fibrotic scar while Iba-1⁺ cells reside predominantly at the margins of optic nerve fibrotic scar. Depletion of hematogenous macrophages results in reduced fibroblast density and decreased extracellular matrix deposition within the fibrotic scar area following ONC. However, retinal ganglion cell degeneration and function loss after optic nerve crush remain unaffected after hematogenous macrophage depletion. We present new and previously not characterized evidence that hematogenous macrophages are selectively recruited into the fibrotic core of the optic nerve crush site and critical for this fibrotic scar formation.