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and proliferation of macrophages in the walls of proinflammatory cytokines such as TNF-α, interferon-γ
human and murine aneurysms, possibly playing a (IFN-γ) and IL-6. [47]
role in the development of IAs. [31] Macrophages also
directly promote degradation of ECM by secreting a Complement
zinc and calcium-dependent family of endopeptidases The role of complement in the mechanism of IA
known as matrix metalloproteinases (MMPs) and formation is not fully elucidated. In one study by
modulate their activity by producing tissue inhibitors a Helsinki group that compared ruptured with
of metalloproteinases (TIMPs), MCP-1 and TNF-α. [32-34] unruptured IA, the expression and activation of
Beside from degrading all kinds of ECM proteins, complement membrane attack complex were greater
these proteinases, particularly MMP-9 secreted also in ruptured samples and was associated significantly
by VSMCs, [35,36] induce macrophage migration and with aneurysm wall degeneration and inflammatory
infiltration across ECM. [37] Overexpression of MMP-9 cell infiltration. [48] These authors showed in another
in the wall of excised IA was first documented by study that complement activation occurs via the
Kim et al., [38] followed by Takemura et al. [39] who later classical pathway as evidenced by the presence of
showed by immunohistochemical analysis of the classical pathway activators (IgG, IgM, C restive
overexpression of MMP-1, -2, and -9 in aneurysm protein, oxidized low-density lipoprotein) in the IA
walls. Moreover, the levels of MMP-2 and -9 were found wall. [49]
to be higher in ruptured compared with unruptured
aneurysms in a series of 30 patients, suggesting that Vascular smooth muscle cells
MMP-mediated excessive breakdown of vessel ECM As mentioned above, VSMCs are crucial in the process
eventually leads to aneurysmal rupture. [40] The central of IAs formation, and rupture. They are mostly found
role of MMPs in the pathogenesis of IAs is further in the medial layer and synthesize the matrix for the
demonstrated by the fact that inhibition of TIMPs structural integrity to the arterial wall. Thinning of this
[50]
promotes aneurysm formation in a rodent model. [41] layer contributes to aneurysm formation and rupture.
Under physiological conditions, MMPs production is In response to endothelial injury VSMCs first migrate
regulated at the level of transcription. An imbalance into the intima where they multiply and give rise to
[51]
between the active MMPs and TIMPs leads to the myointimal hyperplasia. Successively, VSMCs from a
accelerated destruction of connective tissue associated differentiated phenotype whose primary characteristic
with several vascular diseases including IAs. [42] is contraction, dedifferentiation, losing capacity of
expressing contractile genes, like myocardin, acquiring
Neutrophils the capacity to express genes that may affect the rigidity
Other important inflammatory cells migrating to or elasticity of the vascular wall such as collagen alfa2(I)
the site of arterial injury are neutrophils. As for gene (COL1A2) and upregulating proinflammatory
macrophages, they secrete cytokines and MMPs. In genes, such as MMPs, MCP-1, VCAM 1, and IL. [52,53]
addition, they produce peroxidases. [18] The array of This phenotypic modulation of VSMCs is induced
neutrophil-derived cytokines is similar to that of by TNF-α and mediated by Kruppel-like transcription
macrophages, including TNF-α and cxc-chemokines factor 4. [54] Phenotypically modulated VSMCs are no
such as interleukin (IL)-1β. However, unlike longer in spindle shape forming tightly compacted
macrophages, they do not secrete cc-chemokines such bands, but spider-like cells dissociated from each
[55]
as MCP-1. [39] IL-1β and cxc-chemokines are involved other, nonproliferating and noncontractile. Likewise,
in various inflammatory cellular activities such as aneurysmal rupture is associated with degeneration
cell proliferation, differentiation, and apoptosis. and caspase-mediated apoptotic loss of VSMCs of the
Upregulation of IL-1β in animal models of IAs is aneurysm wall. [17,56,57]
associated with aneurysm formation and progression
by reduced collagen biosynthesis in the aneurysm wall Mast cells
both at the transcriptional and post-transcriptional Although best known for their role in allergy and
levels. [43,44] In addition, neutrophils secrete macrophage anaphylaxis, mast cells play an important role in the
inflammatory protein 1-α, which reinforces cytokines’ inflammatory reaction leading to IAs formation and
action to promote inflammatory cell recruitment, rupture mainly via cytokines release and expression
migration, activation, and differentiation. [45] and activation of MMPs. [58] Indeed, IAs formation is
associated with the proliferation and degranulation
Lymphocytes of mastocytes, and ruptured aneurysms wall is richer
Other first-responding inflammatory cells found in in mast cells than unruptured IAs. [59] The finding that
IAs wall are lymphocytes. They infiltrate arterial inhibitors of mast cell degranulation decrease the
wall in early phases of aneurysm formation and inflammatory reaction in aneurysm walls and block
rupture. [46] They are involved in the production of the progression of IAs in mice further support the

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 61