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inflammatory cells.
39,40,45
Matrix deposition, on the other hand, involves
fibroblasts that invade the extracellular matrix and secrete matrix compo-
nents; when uncontrolled, this process contributes to fibrosis. In a mouse
model of pulmonary fibrosis,
b
-arrestin-1 or -2 knockout mice were protec-
ted from excessive matrix deposition, resulting in protected lung function
and heightened survival. Knockdown of either
b
-arrestin in fibroblasts from
patients with pulmonary fibrosis inhibited their migration and invasive
behavior.
46
Thus,
b
-arrestin-dependent chemotaxis
in vivo
contributes to
recruitment of inflammatory cells and matrix depositing fibroblasts, which
can result in chronic inflammation and fibrosis.
In contrast to the studies on airway inflammation, sepsis-induced inflam-
mation may utilize
b
-arrestins in the opposite capacity. Recent studies reveal
that
b
-arrestin-2 appears to negatively regulate tissue damage and mortality
resulting from sepsis.
47
These studies did not deal with
b
-arrestin-stimulated
chemotaxis, but rather production of inflammatory mediators important for
resolving bacterial infections. Release of these cytokines may be dependent
upon the G-protein signaling arm of chemokine receptors and thus inhibited
by
b
-arrestins. It is important to bear in mind that the role of
b
-arrestins in
processes requiring chemotaxis
in vivo
is far more complicated than their role
in chemotaxis
in vitro
. Depending on the physiological scenario and the
receptor being activated, the classical role of
b
-arrestins as terminators of
G-protein signaling or their role as facilitators of chemotaxis may dominate.
7. CONCLUDING REMARKS
Although it has been over a decade since the demonstration that
b
-arrestins are important for chemotaxis downstream of numerous GPCRs,
much remains to be elucidated regarding the underlying molecular mech-
anisms. Clearly, receptor turnover at the hands of
b
-arrestin-dependent
endocytosis is important, but evidence suggests that the story is far more
complicated.
b
-Arrestins are capable of regulating a barrage of cellular activ-
ities essential for cell migration and, in so doing, controlling the localization
of these activities. Since so many of the signals generated during cell migra-
tion must be tightly controlled both spatially and temporally, it stands to rea-
son that the role of
b
-arrestins as signaling scaffolds is equally important in
cell migration. Given the plethora of biological responses, from inflamma-
tion to neuronal development to cancer, that are controlled by
b
-arrestin-
dependent regulation of actin assembly and chemotaxis, gaining a deeper
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