Macrophage infiltration in the saccular intracranial aneurysm wall as a response to locally lysed erythrocytes that promote degeneration

Abstract

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 aSMAþ cells, reflecting loss of mural smooth muscle cells ([SMCs]; r ¼ -0.592, p < 0.001), wall degeneration (p ¼ 0.008), and rupture (p ¼ 0.005). GPA correlated with high numbers of CD163þ and CD68þ phagocytes (r ¼ 0.65 and r ¼ 0.54, p 0.001 for both). CD163þ 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 ¼ 0.014) was detectable by MRI. An additional 11 sIAs 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 T1-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.