Biology Reference
In-Depth Information
initial findings suggest that deficiency in
b
-arrestins may not affect TGF-
b
-
induced matrix production.
131
Further analysis, such as prolonged treatment
with TGF-
b
, may shed some light on the role of TGF-
b
and
b
-arrestins
in inflammatory and fibrotic diseases. In addition,
b
-arrestins have been
shown to regulate the orexin-1 receptor
132
and the TCR/CD28 coreceptor
complex.
133
Through interactions with these signaling pathways,
b
-arrestins
regulate inflammatory responses.
6. ROLE OF
b
-ARRESTINS IN HUMAN DISEASES
The involvement of
b
-arrestins in a number of inflammatory diseases
has been investigated using human tissues and animal models.
Table 14.1
summarizes the animal models of inflammatory disease that have been stud-
ied using
b
-arrestin 1 or
b
-arrestin 2 knockout mice.
6.1. Pathogen recognition and clearance
b
-Arrestins play a role in bacterial-induced inflammation and clearance,
such as in sepsis,
34,134,135
and
Cryptococcus
infections.
27
For example, mice
deficient in
b
-arrestin-2 showed decreased mortality and reduced infections.
Therefore, inhibition of
b
-arrestins may be used to limit bacterial and fungal
infections in some instances.
27,69
6.1.1 Neisseria meningitidis
N. meningitidis
, a commensal bacterium causing cerebrospinal meningitis, is
an intracellular human-specific pathogen that functions through Type IV
pilus-mediated adhesion to human brain endothelial cells, leading to the
opening of intercellular junctions and allowing meningeal colonization.
136
The signaling receptor activated by the pathogen may be the
b
2AR.
69
Stud-
ies have suggested that the
b
2AR/
b
-arrestin signaling pathway may mediate
bacterial colonization.
136,137
Type IV pili of
N. meningitidis
are able to acti-
vate the
b
2AR/
b
-arrestin signaling pathway, thus recruiting the polarity
complex and the cell junction proteins and allowing the opening of a para-
cellular route in endothelial cells.
138
By this process,
N. meningitidis
is able to
cross the blood-brain barrier and affect the central nervous system.
138
Acti-
vation of
b
2AR endocytosis with specific agonists prevents signaling events
downstream of
N. meningitidis
adhesion and inhibits bacterial crossing of the
endothelial barrier.
69
Therefore, targeting the
b
2AR/
b
-arrestin signaling
pathway may be used for treatment and prevention of meningococcal
infection.
69
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