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and rupture. The contributions of individual cell and in all of the ruptured IAs. Using electron
types are detailed, with special attention paid to the microscopy, the authors were able to demonstrate
cytokine and molecular profiles. The role of magnetic an association between advanced deterioration in
resonance imaging (MRI) as a means by which to the wall of ruptured aneurysms and the infiltration
evaluate aneurysm-associated inflammation is of leukocytes and macrophages. [31] Frösen et al. [12]
reviewed. Finally, we discuss leukocytes as potential also observed more prominent leukocyte infiltration
targets of pharmacologic intervention. in ruptured IAs when compared to unruptured IAs.
These findings suggest that the structural architecture
DETECTION AND INVESTIGATION OF of ruptured aneurysms differs from that of unruptured
LEUKOCYTES IN HUMAN INTRACRANIAL aneurysms. Furthermore, leukocyte invasion appears
ANEURYSM PATHOGENESIS to be a mediator of this change and a potential driving
impetus behind the progression to aneurysm rupture.
Currently, the literature suggests that leukocyte
infiltration of the intracranial vasculature may play ROLE OF MACROPHAGES
various roles in the prolonged formation and acute
rupture of IAs. Frösen et al. [12] reported that IA walls Animal and clinical studies have identified macrophages
obtained less than 12 h after rupture demonstrated as important contributors to the formation and rupture
T-cell and macrophage infiltration, as well as VSMC of aneurysms. These cells participate in the synthesis
proliferation, indicating a chronic process that preceded and secretion of matrix metalloproteinases (MMPs)
rupture. In addition, the observation of leukocytes and elastases, which play significant roles in the
spread throughout aneurysm walls supports their role degradation of the extracellular matrix and internal
in the global deterioration of the vessel and suggests elastic lamina. Histopathological analysis of both
that their prominence in ruptured aneurysms is not an unruptured and ruptured aneurysms has repeatedly
acute response to the sudden event. [31] identified macrophage infiltration within the aneurysm
walls. [12,20,37] In addition, Ruzevick et al. [38] observed
Transcriptome analysis of control vessels and IAs the pro-inflammatory haptoglobin 2-2 genotype to
demonstrates upregulation of gene expression of the be associated with larger aneurysms and increased
pro-inflammatory cytokines associated with leukocyte macrophage infiltration within the aneurysm walls.
infiltration within aneurysm walls. [15,32-36] Weinsheimer
et al. [35] in an analysis of IAs obtained from autopsies Macrophage-depleted mice have been shown to have a
within 24 h of death, showed upregulation of moderate protective advantage from aneurysm formation
several pro-inflammatory genes, including, adherens and rupture, suggesting macrophages play a critical role
junction, the mitogen-activated protein kinase in the aneurysm pathogenesis. [13,39] Corroborating this
pathway, and Notch signaling. Krischek et al. [36] hypothesis are two animal studies investigating the
investigated gene expression on 10 IAs (6 ruptured role of monocyte chemoattractant protein 1 (MCP-1),
and 4 unruptured) and determined that the most an important macrophage chemoattractant that has
significantly upregulated pathway was antigen been studied in atherosclerosis and abdominal aortic
processing. Shi et al. [15] interrogated 6 IAs using the aneurysms (AAA). [40,41] By using MCP-1 knockout (KO)
[9]
[13]
illumina microarray platform and determined focal mice, both Aoki et al. and Kanematsu et al. were able
adhesion, extracellular matrix receptor interaction, cell to demonstrate a decrease in aneurysm formation and
communication, inflammatory response, and apoptosis macrophage accumulation. Aoki et al. also reported
[9]
to be the most significant functional pathways that inhibiting MCP-1 activity using a dominant
involved in IA pathogenesis. These findings indirectly negative mutant of MCP-1 resulted in the inhibition
implicate leukocyte infiltration as a major contributor of aneurysm progression in rats. MCP-1 deficient mice
to aneurysm genesis and progression. also demonstrated decreased macrophage accumulation
and expression of MMP-2 and MMP-9. A recent
[9]
Finally, immunohistochemical analysis of the study conducted by Chalouhi et al. [42] surveyed the
animal model and human aneurysms has repeatedly cytokines and chemokines in aneurysm lumen blood
demonstrated leukocytes within the aneurysmal walls. and found an increase in chemoattractant cytokines
Chyatte et al. [20] reported the presence of macrophages interleukin-7 (IL-7), IL-8, and MCP-1, suggesting active
and T-lymphocytes within the walls of unruptured recruitment of inflammatory cells into the aneurysm.
aneurysms. Ruptured aneurysms have also been found
to harbor T-lymphocytes and macrophages within Nuclear factor-κB (NF-κB) is a family of transcriptional
their walls. [12,31] In a study of ruptured and unruptured factors involved in regulating the expression of a
IAs, Kataoka et al. [31] observed leukocyte infiltration, variety of inflammatory factors including MCP-1.
particularly macrophages, in 50% of the unruptured Aoki et al. [43] investigated the role of NF-κB in the

108 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015