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Koseki et al. Inflammatory cells in intracranial aneurysm

lesions. Given that the high wall shear stress loaded rich lesions from ferumoxytol-MRI. Intriguingly, anti-
[52]
[13]
on bifurcation sites of intracranial arteries where IA inflammatory drugs (non-steroidal anti-inflammatory
forms is considered to be a trigger of IA formation drugs) decreased signals in this imaging method, which
through extensive studies conducted in mainly was accompanied with a decrease in the macrophage
3D-computational fluid dynamics analyses of human count within lesions, suggesting that macrophage-
[53]
IA lesions, [10,46-48] one potential factor triggering NF-κB- imaging using ferumoxytol-MRI can positively reflect
dependent MCP-1 expression in endothelial cells is macrophage-rich or poor lesions. Importantly, these
presumably this hemodynamic force. However, further findings suggest the potential of this imaging method as
studies are needed in order to corroborate whether a surrogate marker to non-invasively monitor disease
macrophages indeed migrate across endothelial cells activity. Unfortunately, ferumoxytol has a risk of a fatal
during IA formation and progression. Given these allergic reaction and the FDA has strengthened the
findings, IA is now considered to be a macrophage- warning concerning usage of this drug as a contrast
mediated inflammatory disease of the intracranial agent for diagnostic purposes. Therefore, a novel
arteries. Therefore, macrophages could be a target in contrast agent for macrophage imaging with excellent
the development of a novel diagnostic method and in biocompatibility and adequate safety is needed. In
the development of a therapeutic drug. addition, because red blood cells contain a large
amount of iron in the hemoglobin, macrophage-
MACROPHAGE IMAGING imaging using iron-containing particles need to be
evaluated after the subtraction of signals derived from
Given the devastating consequences of an aneurysmal red blood cells in the vasculature. Unfortunately, these
subarachnoid hemorrhage as well as the relatively low subtraction procedures are often time-consuming and
annual risk of rupture, it is crucial to appropriately make interpretation quite difficult. Hence, to overcome
[2]
select rupture-prone IAs among many unruptured the technical limitations related to iron-particle-based
IAs while avoiding unnecessary surgical intervention macrophage-imaging methods, positive contrast
through the proper estimation of the rupture risk for agents such as nano-particles containing gadolinium
each lesion. For example, a qualitative evaluation may be beneficial. Furthermore, with the use of a
using non- or minimally-invasive magnetic resonance nano-particle based technique, a novel drug delivery
imaging (MRI) of IA lesions could be a candidate system targeting macrophages may be possible. If
diagnostic method. Given the crucial contribution so, IAs with abundant macrophage infiltration can be
of macrophage-mediated inflammatory responses selectively targeted and treated by a cytotoxic agent in
to the pathogenesis of IAs, [10,36,45,49] macrophages order to reduce macrophage-mediated inflammation in
as well as factors secreted from or factors recruiting IA lesions.
macrophages can be considered potential targets for
imaging. Macrophages are an antigen-presenting cell; As described above, macrophages have a wide range
thus, macrophages actively search for and engulf of subpopulations with different characteristics.
[44]
foreign bodies by nature. Through their phagocytic In human IA lesions, the M1 and M2 subpopulations
activity, contrast agent-engulfing macrophages can are detected using immunostaining. Further, as
[16]
be theoretically visualized using MRI. Indeed, many indicated in the previous report demonstrating a
studies have demonstrated the application of this marked predominance of M1 over M2 in ruptured IAs
type of imaging technique for macrophage-mediated compared to that in unruptured lesions, a particular
[16]
pathological conditions or diseases, including infection subpopulation of macrophages may alone contribute
and atherosclerosis. [50,51] In these studies, ferumoxytol, to the rupture of IAs. If so, the detection of this specific
which is an ultra-small superparamagnetic particle of subpopulation would be helpful in discriminating
iron oxide approved by the Food and Drug Administration rupture-prone IAs from stable lesions. Thus, next-
(FDA) for the treatment of Iron Deficiency Anemia due generation imaging modalities for subpopulation-
to chronic renal failure, was applied as a contrast agent. specific visualization of macrophages are desired.
Recently, the use of macrophage imaging for IAs has In addition, MRI contrast agents that target enzymes
been reported. [52-55] In a series of reports, Ferumoxytol produced by inflammatory cells may be useful in
was intravenously administered to patients with pre- diagnosing rupture-prone ‘dangerous’ lesions as
diagnosed unruptured IAs and ferumoxytol-engulfing suggested in a recent review article. For example,
[55]
macrophages were visualized using a T2 star weighted myeloperoxidase is an enzyme produced by myeloid-
image. In addition, in order to validate the MRI findings, linage cells such as neutrophils. Enzymatic activity of
the presence of iron particles was histologically this protein can be monitored by MRI using gadolinium-
confirmed using Prussian blue staining of CD68 chelating bis (5-hydroxytrytamide) derivatives of
+
macrophages in the IA walls identified as macrophage- diethylenetetraamine pentaacetic acid as a contrast
Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ August 31, 2016 177