Biology Reference
In-Depth Information
3
Selective Pro-Inflammatory
Activation of Astrocytes by High
Mobility Group Box 1 Protein
Signaling
Marco Pedrazzi, Edon Melloni, Bianca Sparatore
Department of Experimental Medicine—Biochemistry Section,
University of Genova, Genova, Italy
3.1 Introduction
High mobility group box 1 (HMGB1) protein, originally identified as a chromatin
component, is highly conserved in mammals and particularly abundant in develop-
ing tissues, in proliferating and transformed cells
[1-3]
. More recently, HMGB1 has
been identified in the cytoplasm and in the extracellular compartment of different acti-
vated or dying cells. Specifically, a number of cell types actively export HMGB1 when
exposed to inflammatory agents and oxidative stress or when they interact with other
cells
[4-7]
. The active cell release of HMGB1 involves sequential steps. At first, an
enhanced nucleocytoplasmic shuttling of the protein is triggered by hyperacetylation
and phosphorylation at specific serine residues, mediated by the calcium/calmodulin-
dependent protein kinase (CaMK) IV
[8,9]
. Subsequently, cytosolic HMGB1 is concen-
trated into secretory lysosomes and released when appropriate stimuli trigger lysosome
exocytosis
[10]
. However, depending on the cell type, a passive release of HMGB1 can
occur during the course of apoptosis as well as necrotic death
[11,12]
. In the last condi-
tion, the release of the protein is preceded by a poly-ADP-ribose polymerase (PARP)-
dependent nuclear-to-cytosolic translocation of HMGB1
[13]
. HMGB1 shows heparan
sulfate-rich proteoglycan binding properties that limit its rate of extracellular diffusion
[14]
. Depending on its local concentration and on the site of cell release, HMGB1 can
exert regenerative or inflammatory functions by engagement of some membrane pro-
teins, including the receptor for advanced glycation end products (RAGE) and the toll-
like receptors (TLRs) 2 and 4, involved as HMGB1-signaling mediators in different
cell types
[15,16]
. Hence, HMGB1 promotes tissue development and regeneration by
activating cell migration, differentiation, proliferation, and immune responses directed
against dying cell antigens, and also sustains pathological conditions as an enhancer of
inflammatory responses, tumor cell invasiveness, and lethal endotoxemia
[17-21]
.
