Macrophage Infiltration in the Saccular Intracranial Aneurysm Wall as a Response to Locally Lysed Erythrocytes That Promote Degeneration

Saccular intracranial aneurysm (sIA) rupture is often fatal. Rupture-prone sIA walls are infiltrated by macrophages expressing hemoglobin-receptor CD163, suggesting a role for erythrocyte lysis in the degenerative remodeling predisposing to rupture. We therefore studied erythrocyte remnants in 16 unruptured and 20 ruptured sIA walls using histology and immunohistochemistry. Glycophorin A (GPA), an erythrocyte membrane protein, was present in 34/36 (94%) sIA walls and correlated with loss of proportional to SMA(+) cells, reflecting loss of mural smooth muscle cells ([SMCs]; r = -0.592, p < 0.001), wall degeneration (p =0.008), and rupture (p =0.005). GPA correlated with high numbers of CD163(+) and CD68(+) phagocytes (r =0.65 and r = 0.54, p <= 0.001 for both). CD163(+) phagocytes were mostly HLA-DR. Interestingly, single SMCs expressed HLA-DR and also CD163 was expressed in sporadic SMCs, which may reflect their response to hemoglobin accumulation. GPA associated with iron (p =0.014) was detectable by MRI. An additional 11 slAs were therefore imaged ex vivo with a 4.7 T MRI prior to histology. In the sIA walls, high GPA and iron accumulation associated with signal intensity in Tl-weighted gradient echo MRI. We conclude that accumulation of lysed erythrocytes is a potential driver of inflammatory response in the sIA walls and is associated with the degenerative wall remodeling, thereby predisposing to rupture.