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Koseki et al. Inflammatory cells in intracranial aneurysm

cells as well as T helper 1, 2, and 17 cells (Th1, Th2, the presence of mast cells and IA progression, the
and Th17). Some T cells function as a node of acquired researchers treated rats with emedastine difumarate
immunity and regulate inflammatory responses in (1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-
a coordinated manner with other cell types in the 1,4-diazepin-1-yl)-benzimidazole difumarate) and
microenvironment. As expected, T cells play a crucial tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic
role in various diseases, including inflammatory acid), two widely-used inhibitors for limiting mast cell
and autoimmune diseases. The accumulation of degranulation. Inhibition of mast cell degranulation
[20]
T cells in human IA lesions has been pathologically effectively reduced lesion size and degenerative
demonstrated, suggesting the contribution of this cell changes of the media through the inhibition of
type to the rupture of IAs. [14,15] Although a recent study inflammatory responses, including reduced NF-
has demonstrated the predominance of Th1 and Th17 κB activation, monocyte chemoattractant protein-1
subsets over Th2 in ruptured IAs, the detailed role (MCP-1) expression, macrophage infiltration, matrix
[21]
of T cells in the pathogenesis of IAs, including which metalloproteinases (MMPs) and IL-1β expression,
subset/subtype of T cells regulates IA formation and which facilitate pathogenesis. [10,13,36-39] Moreover,
rupture, remains to be elucidated. in vitro experiments using a primary culture in
which vascular smooth muscle cells and mast cells
Mast cells prone to degranulation are co-cultured, confirmed
Mast cells are characterized by a large number of the contribution of mast cell degranulation to the
cytoplasmic granules and are well recognized as activation of medial smooth muscle cells. Given
[35]
mediators of certain types of inflammation including that factors suppressed by the administration of
allergic inflammation. [22,23] Mast cells play a role in degranulation inhibitors are known to facilitate IA
inflammation through degranulation of cytoplasmic formation and progression, [10,13,36-39] mast cells or mast
granules, which contain a variety of cytokines and cell degranulation inhibitors may be a therapeutic
pro-inflammatory factors such as tumor necrosis target for IA treatment. It is encouraging that mast
factor-alpha (TNF-α), interleukin (IL)-1β, IL-3, IL-4, cell degranulation-inhibitors are already widely used
IL-6, IL-8, IL-13, and transforming growth factor-beta as anti-allergic drugs; thus, medical therapy targeting
(TGF-β). [24-29] Once mast cells are activated, they mast cells may be possible in near future.
release large amounts of pro-inflammatory factors
from the granules into the extracellular space, resulting Neutrophils
in the induction of inflammatory responses within the Neutrophils, defined using surface markers such as
microenvironment. Mast cells significantly participate CD11b, Ly-6G and Ly-6C, are antigen-presenting
in the pathogenesis of various inflammation- cells. This cell type is recruited by chemoattractant
related diseases, including vascular diseases such factors such as chemokine (C-X-C motif) ligand
as atherosclerosis, [24,30-33] via the release of pro- 1 (CXCL1) and is present in the inflammatory
[40]
inflammatory factors from granules. microenvironment, migrating to inflammation sites and
exacerbating inflammatory responses by secreting
In the case of IA, the presence of mast cells in human various pro-inflammatory factors in response to
IA lesions has been demonstrated. [16,19] Hasan et al. cytokines present in situ. Factors released from
[16]
further demonstrated that the number of mast cells neutrophils include proteases and digestive enzymes
located in IA lesions is larger for ruptured compared such as myeloperoxidase, collagenase, elastase, and
to unruptured IAs, suggesting a role for mast cells cathepsin. Neutrophil turnover during inflammation
[20]
in the rupture of IAs. In addition, Ollikainen et al. is usually rapid; therefore, this cell type is traditionally
[19]
demonstrated a positive correlation between the believed to be a mediator of the acute inflammatory
number of mast cells present in IA lesions and response. However, recent studies have revealed
neovascularization and iron deposition (presumably the contribution of neutrophils to the pathogenesis
due to microhemorrhage), suggesting the contribution of diseases with long-lasting inflammation, referred
of mast cells to degenerative changes in the media. to as chronic inflammatory diseases. For example,
However, the exact contribution of mast cells to the neutrophils are the most abundant cell type in colitis-
pathogenesis of IAs is difficult to discern from studies associated colon cancer induced in mice and have been
using human specimens; thus, the pivotal role of mast shown to be as a major source of cytokines regulating
cells to the pathogenesis of IA has been clarified inflammatory responses, including TNF-α and IL-6,
using animal IA models. [34,35] These studies have which contribute to the transformation/proliferation of
demonstrated an increase in the number of mast cells cancer cells. [41,42] The crucial contribution of neutrophils
in IA lesions during progression of the disease. In to the pathogenesis of cancer has been clarified in
order to demonstrate a causal relationship between a study demonstrating that the genetic depletion of
Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ August 31, 2016 175