Page 68 - Read Online

remodeling and the development and rupture of IAs. types to respond to injury, but it also regulates the later
This approach may provide effective tools to predict immune response. [18] The role of these inflammatory
the individual risk of aneurysmal rupture more reliably cells in IAs formation is demonstrated by the fact that
than statistical methodology. macrophage depleted mouse displays a lower risk
of IAs. [19] Macrophage action on the arterial wall is
METHODS OF THE REVIEW mediated by secretion of cytokines and proteinases.

The literature review was conducted using Medline Cytokines are peptides, proteins, and glycoproteins
and EMBASE searches that included works published that mediate inflammatory and immune response. [20-22]
between 1980 and 2014. The terms “IA” and “cerebral Several cytokines secreted by macrophages have been
aneurysm” were used as text words and MESH headings found involved in the pathogenesis of IA especially
with appropriate subheadings. A further search was monocyte chemoattractant protein-1 (MCP-1), tumor
performed to link cerebral and IAs and the following key necrosis factor alpha (TNF-α), stromal cells derived
words: inflammation, hemodynamic(s), remodeling, factor-1 (SDF-1/CXCL12). MCP-1 is a chemotactic
macrophages, neutrophils, lymphocytes, complement, cytokine, also known as chemokine, for monocytes,
VSMCs, mast cells, cytokines, and inflammatory lymphocytes, and some granulocytes secreted by
biomarkers. Textbooks, journal bibliographies, and macrophages. [23] Its implication in the development
conference proceedings were also included. Language of IAs is demonstrated by a decrease of IAs and
restrictions were not used. arterial wall inflammation in MCP-1 knockout
mice. [24] TNF-α is another proinflammatory cytokine
INFLAMMATION AND INTRACRANIAL secreted by macrophages. [18] Experimental data
ANEURYSMS REMODELING suggest a critical role of TNF-α in the formation and
rupture of aneurysms in a murine model of cerebral
The central nervous system is an immunologically aneurysm formation induced by hypertension and a
active environment where a complex set of interactions single stereotactic injection of elastase into the basal
links the various constituents of the immune and cistern. [25] TNF-α knockout mice and those pre-treated
inflammatory system with the constituents of nervous with 3,6’-dithiothalidomide (DTH), a synthesized TNF-α
tissue and vasculature. [15] Aneurysm formation begins inhibitor, had significantly decreased the incidence of
with a hemodynamically triggered endothelial aneurysm formation and rupture as compared to sham
dysfunction where inflammation initiated by nuclear mice. Protein and mRNA expression of TNF-α in the
factor kappa-light-chain-enhancer of activated B cerebral vasculature were not significantly different
cells (NF-κB) activation and imbalance between nitric in TNF-α knockout mice and in those pre-treated
oxide (NO) and peroxynitrite anion (ONOO ) in favor with DTH. However, TNF-α expression was higher in
−
−
of ONOO seem to hold a key role. [16] The following unruptured and the highest in ruptured aneurysms
mounting inflammatory response implicates several when compared to other conditions of aneurysms,
inflammatory cells and mediators and phenotypic where it co-localized to both smooth muscle cells
modulation of VSMCs from a contractile to a and macrophages. SAH occurred between 7 and
pro-inflammatory/pro-matrix remodeling phenotype 21 days following aneurysm induction. Initiation of
with myointimal hyperplasia, inflammation and wall DTH treatment 6 days after aneurysm induction did
degeneration. not alter the incidence of aneurysm formation but
resulted in aneurysmal stabilization and a significant
Several in vitro and in vivo studies found evidences decrease in rupture. Therefore, it can be inferred
that infiltration of inflammatory cells in the arterial that inhibitors of TNF-α could be beneficial in
wall initiates aneurysm formation and promotes its preventing aneurysmal progression and rupture. [25]
rupture through production of inflammatory cytokines, TNF-α upregulates the adhesion molecules such as
adhesion molecules, immunoglobulins, reactive intercellular adhesion molecule-1 (ICAM-1), vascular
oxygen species (ROS), complement and inflammatory cell adhesion molecule-1 (VCAM-1) and E-selectin
cell-induced upregulation of matrix-degrading in ECs, fibroblasts, and SMCs. [26] These adhesion
proteinases, among which macrophages, neutrophils, molecules attract and facilitate migration of leucocytes
and lymphocytes hold a central role. [17,18] through the arterial wall, predisposing to atherosclerosis
and IAs development. [26] Macrophages secrete also
Macrophages another potent chemoattractant cytokine, such as
Monocytes originally produced in bone marrow enter SDF-1/CXCL12. [27-29] Besides promoting angiogenesis by
circulation and infiltrate endothelium at the site of recruiting endothelial progenitor cells from the bone
the hemodynamic injury, where they differentiate into marrow through a CXCR4 dependent mechanism, [30]
macrophages. [18] Macrophage is one of the first cell SDF-1 is associated with angiogenesis and migration

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