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 αSMA+ 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 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.

Biomarkers from circulating neutrophil transcriptomes have potential to detect unruptured intracranial aneurysms

“…Besides these five genes, nine other transcripts ( CD163, TGS1, CYP26B1, ADTRP, OCLN, OLAH , C1QL1, FCRL5, and IGSF23 ) in the 26-transcript classifier reflect complex inflammatory processes, albeit not specifically attributed to neutrophil activation. For example, CD163 , which is abundant in the walls of IAs (but typically associated with macrophages [85, 86]), has been shown to be increased in neutrophils during sepsis [87] and thus could be contributing to vascular inflammation in IA. Expression differences of other transcripts, like TGS1 and CYP26B1 (that are differentially expressed in tuberculosis [88] and juvenile idiopathic arthritis [12], respectively) could be related to neutrophil responses to intravascular perturbations during IA.…”

Identification of potential key pathways, genes and circulating markers in the development of intracranial aneurysm based on weighted gene co-expression network analysis

“…Then the results of ROC curves showed that CD163, FCEREG, FPR1, ITGAM, NLRC4, PDG and TYROBP were potential circulating markers for predicting RIA. Among them, CD163 is a scavenger receptor for hemoglobin-haptoglobin complex phagocytosis [38], it is highly expressed in degenerated and ruptured IA walls [39]. The upregulation of FPR1 can induce the synthesis of neutrophils mediated by Mac-1 through fpr related Gi protein and b-arrestin signalling pathway, thus aggravating the development of abdominal aortic anerysm (AAA) [40], which suggest it may also participate in the development of IA.…”

Vascular Macrophages as Therapeutic Targets to Treat Intracranial Aneurysms

“…Previously, Froesen and colleagues demonstrated differences in CD68+ and CD163+ macrophages in human ruptured and unruptured ICAs (29). Intriguingly, CD68+ and CD163+ (hemoglobin-haptoglobin scavenger receptor) macrophages, mostly HLA-DR-, co-localize with glycophorin A (a component of the erythrocyte membrane) and infiltrate ICAs as a response to a luminal thrombus trapped and lysed erythrocytes, and may promote degenerative arterial wall remodeling (46). In a mouse model of ICAs, M1 (F4/80+ iNOS+) dominate over M2 (F4/80+ Arg1+) during aneurysm development (47).…”