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The M1 population is pro-inflammatory and secretes treated with an antineutrophil-antibody showed
[63]
high levels of IL-2, IL-23, IL-6, IL-1, and TNF-α. The M2 a decreased number of macrophages compared to
population is antiinflammatory and secretes high levels wild-type (WT) mice. [55] Furthermore, depletion of
[63]
of IL-10. Hasan et al. examined 10 patients with IAs (5 neutrophils attenuated the size and incidence of AAA.
unruptured and 5 ruptured) for the presence of M1 and Diminished macrophage infiltration in aneurysms
M2 macrophage populations. The authors demonstrated of neutrophil-depleted mice is not associated with a
a predominance of M1 over M2 macrophages within decrease in chemoattracts such as MCP-1 and MIP-1α.
[55]
the walls of ruptured aneurysms and observed an This suggests that additional mediators are contributing
increase in mast cells in ruptured aneurysms compared to this complex interaction. Importantly, there was no
to unruptured aneurysms. The authors hypothesized difference in expression of MMP-2 and MMP-9, despite
that the imbalance between M1 and M2 may be in part a decrease in macrophage infiltration.
due to the effects of mast cells. Given these results, the
interplay between M1 and M2 phenotypes appears to be The presence of neutrophils was recently reported
important in the aneurysm pathogenesis and warrants by Marbacher et al. [70] using a decellularized rat
further investigation. aneurysm model. This rat model simulated the loss
of mural cells (endothelial and VSMCs), a hallmark
ROLE OF MAST CELLS of ruptured cerebral aneurysms. [12,31] The ruptured

aneurysms displayed marked adventitial fibrosis
Mast cells are resident leukocytes that contain and inflammation, complete wall disruption, and
cytoplasmic granules rich in histamine and heparin, as increased neutrophil accumulation in unorganized
well as, the pro-inflammatory cytokines, TNF-α, IL-1, intraluminal thrombus. [70] Neutrophils trapped
IL-3, IL-4, IL-5, IL-8 and IL-13, and transforming growth in unorganized thrombus are a major source of
factor-beta. [64,65] Mast cell degranulation and release of matrix-degrading proteases. Intraluminal thrombus
cytokines has been linked with vascular inflammatory is a site of protease and cytotoxic compound release
processes, such as, atherosclerosis and AAAs. [66,67] Recent leading to wall inflammation and subsequent matrix
investigations have targeted mast cells as contributors degradation. [55,71]
to IA genesis and progression. In a study conducted by
Ishibashi et al., an increase in the total number of Myeloperoxidase (MPO) is a peroxidase enzyme that
[65]
mast cells during IA formation was observed using a rat catalyzes the formation of a number of reactive oxidant
model. Mast cell degranulation inhibitors suppressed species and is primarily produced by neutrophils. [72]
IA progression through attenuation of the local chronic Along with a well-known role in host mechanisms
inflammatory response, as was evident from decreased against pathogens, MPO has recently been implicated
NF-κB activation, macrophage infiltration, and expression in the initiation and destabilization of atherosclerotic
[65]
of MCP-1, MMPs, and IL-1β. In addition, Ollikainen [73] [74]
et al. [68] demonstrated that mast cells in the wall of plaques. In a study conducted by Gounis et al.,
IAs were associated with histopathological changes MPO was detected in all three ruptured IAs and 10 out
[74]
[74]
consistent with wall remodeling, lipid accumulation, of 20 unruptured IAs. Additionally, Gounis et al.
and inflammatory cell infiltration. Finally, Hasan et al. demonstrated that MPO positivity was a significant
[63]
observed increased mast cells in ruptured IAs relative to predictor of 5-year aneurysm rupture rate. An emerging
unruptured IAs. Taken together, these studies indicate picture suggests a key factor in aneurysm formation
that mast cell degranulation play a critical role in and rupture is the ongoing inflammatory process
aneurysm formation and may contribute to IA rupture. mediated by infiltration of leukocytes. This suggests
that MPO may play an important role in the aneurysm
ROLE OF NEUTROPHILS pathogenesis. Therefore, MPO may also serve as a
potential biomarker.
Neutrophils are recruited to sites of injury and are
a hallmark of acute inflammation. Although the Neutrophils represent a potential therapeutic target for
contribution of neutrophils in IA formation is largely pharmacologic interventions designed at preventing
undefined, evidence from investigations into AAA aneurysm progression and rupture. Hannawa et al. [69]
pathogenesis offers insight into their role. Animal demonstrated suppressed AAA formation in L-selectin
models have demonstrated progressively increasing KO mice. L-selectin, an adhesion molecule expressed
neutrophil infiltration into the walls of AAAs over the on the surface of most leukocytes, is responsible for
course of aneurysm development. [55,69] the recruitment of immune cells. [75-77] Hannawa et al. [69]
postulated that the diminished AAA formation seen in
Neutrophil recruitment to the vascular wall may WT mice compared with the L-selectin KO mice is most
be associated with macrophage infiltration. Mice likely due to the impaired recruitment of neutrophils

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