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Koseki et al. Inflammatory cells in intracranial aneurysm

C-X-C chemokine receptor 2, the receptor for CXCL1, M2 ameliorating inflammation. Hasan et al. found
[16]
resulted in a significant reduction of tumorigenesis. [41] that, in unruptured IAs, M1 and M2 populations were
similar, but in ruptured IAs, the balance shifted to M1-
In case of IAs, the presence of neutrophils in IA lesions predominance over M2, indicating a role for M1 in the
has been demonstrated both in human specimens and rupture of IAs. However, careful attention is needed
[17]
in animal models. [17,37] In human IAs, myeloperoxidase- regarding the role of specific macrophage subsets in
positive cells, including neutrophils, are abundantly the rupture of IAs because subarachnoid hemorrhage
present in IA lesions. Genetic loss of myeloperoxidase as the consequence of rupture robustly induces acute
[17]
in mice significantly reduces not only the incidence inflammation, and thereby presumably shifts the
of IAs, but also delays the onset of subarachnoid balance among macrophage subsets.
hemorrhage. This suppressive action due to the loss of
myeloperoxidase is accompanied with the suppression Recent experimental studies using animal IA models
of CXCL1 and other pro-inflammatory factors. These have clarified the crucial role of macrophages in IA
results suggest a role for myeloperoxidase, presumably formation and progression. Using a rat model, Aoki et al.
[37]
produced by neutrophils, in the incidence and rupture demonstrated that macrophages are the major
of IAs. Intriguingly, as the loss of myeloperoxidase inflammatory cell type in IA walls with the remaining
suppresses CXCL1 expression, myeloperoxidase may cell types consisting of T lymphocytes and neutrophils.
contribute to the formation of a positive feedback loop The authors also demonstrated the presence of mast
among neutrophils, which amplifies and exacerbates cells in IA walls in an experimental model; however,
inflammation. Thus, myeloperoxidase may function macrophages occupied the majority of inflammatory
to form a vicious cycle leading to the progression of cells. In order to examine the contribution of
[35]
IAs. Therefore, myeloperoxidase, or another factor macrophages to IA formation and progression, mice
regulating the activity of neutrophils, could be an ideal deficient in monocyte chemoattractant protein-1
therapeutic target in the treatment of IAs. (MCP-1), a major chemoattractant for macrophages,
were subjected to an IA model. The genetic loss of
[36]
Macrophages MCP-1 almost completely inhibited the infiltration of
Macrophages, defined by the expression of surface macrophages in lesions and significantly suppressed
markers including CD11b, CD68, CD163, are also IA formation to the level seen in un-treated wild
antigen-presenting cells. It is, of course, the major type mice. The effect of a genetic loss of MCP-
[43]
[36]
cell type evoking inflammatory responses. The 1 on IA formation has also been demonstrated in
accumulation of macrophages in human IA lesions has another study by Kanematsu et al. In addition,
[45]
been demonstrated. Chyatte et al. demonstrated Aoki et al. administered the dominant-negative
[15]
[36]
that number of macrophages was larger in IA lesions form of MCP-1, known as 7-ND, in a rat IA model by
than in control arterial walls, and thus proposed a role injecting expression plasmid in the femoral muscle,
for macrophages in the formation and rupture of IAs. and demonstrate a suppression of IA formation and
Frösen et al. analyzed the pathology of surgically- progression, further confirming the crucial role of MCP-
[14]
dissected IA walls and found that macrophage 1-mediated macrophage infiltration in IA formation
infiltration, apoptosis, the loss of endothelial cells, and progression. In the IA walls of MCP-1-deficient
thrombosis in the lumen, and the proliferation of mice, the inflammatory response, including NF-κB
medial smooth muscle cells were more frequently and activation as well as iNOS and MMP-9 induction, was
robustly observed in ruptured IAs than in unruptured remarkably ameliorated compared with that of wild
IAs, suggesting a role for macrophages in the rupture type mice, supporting the role of macrophages as
[36]
of IAs. Furthermore, as macrophage infiltration was an inducer of inflammation in lesions. The importance
correlated with the proliferation of medial smooth of macrophages in the pathogenesis of IAs is also
muscle cells and both were increased in ruptured IAs supported by Kanematsu et al. [45] in which the
collected within 12 h after rupture, the authors proposed pharmacological depletion of macrophages using
an additional role of macrophages in the repair of the clodronate liposome remarkably suppressed IA
arterial walls of IA lesions. Hasan et al. examined formation in mice. MCP-1 expression overlaps with
[14]
[16]
macrophage subsets (M1 and M2) in IA walls. M1 NF-κB in endothelial cells during the early stage of
and M2 are defined according to the expression of IA formation, indicating that NF-κB-dependent
[36]
several markers with inducible nitric oxide synthase MCP-1 expression and trans-endothelial migration
(iNOS) expressed in M1 and CD163 expressed of macrophages occurs via MCP-1. Indeed, mice
in M2 macrophages. Traditionally, M1 and M2 deficient in the NF-κB p50 subunit show significantly
[44]
macrophages are believed to function oppositely less induction of MCP-1 in lesions, supporting the
in inflammatory settings with M1 exacerbating and dependency of NF-κB on MCP-1 expression in
176 Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ August 31, 2016