b-Arrestins in the Immune System - Progress in Molecular Biology and Translational Science - page 362

in monocytes. 120

b -Arrestin-2 mediated redistribution of CD14 and the
TLR4/CD14 complex. 120 The b 2AR regulates TLR4-induced late-phase
NF- k B activation. 121 Furthermore, recent studies suggest there is cross
talk between TLRs and chemokine receptors. TLR2 activation leads
to b -arrestin-mediated endocytosis of CCR1, CCR2, and CCR5 on
human blood monocytes, providing a molecular mechanism for inhibiting
monocyte migration after pathogen recognition. 122 Moreover,itseems
that TLRs also directly regulate b -arrestins. For instance, activation of
TLR2 and TLR4 significantly decreased b -arrestin 2 protein expression
in macrophages. 24

GPCR signaling TLR signaling

LPS

Chemokine
Chemokine receptor

TLR

MyD88

Arrestin

Arrestin

TRAF6
autoubiquitination
and oligomerization

MAPK

Desensitization
Internalization

TRAF6 Endosome

Internalization

Signaling

NF- B

activation

κ

Leukocyte chemotaxis
Cytokine production

Leukocyte chemotaxis
Cytokine production

Chromatin
modification

Cytokine

Leukocyte chemotaxis
Cytokine production

Cytokine

Figure 14.1 b-Arrestins regulate GPCR and TLR signaling during inflammation. Upon
binding of chemokines to their respective receptors, b-arrestins are recruited to the
receptors and regulate chemotaxis of leukocytes into inflammatory sites and cytokine
release in two ways: mediating receptor desensitization and internalization, and acting
as signaling scaffolds to facilitate numerous effector pathways. Classically, LPS - TLR
interaction induces signaling cascades including TRAF6 and NF-kB activation, leading
to an inflammatory response. LPS - TLR binding also recruits b-arrestins and the latter
mediate TLR signaling through regulating TRAF6 and NF-kB, as well as chromatin mod-
ification. Furthermore, b-arrestins are able to mediate the cross talk to chemokine
receptors.