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on oligodendrocytes and induced CXCL1 on hypertrophic astrocytes in multiple scle-
rosis have also been proposed as a novel mechanism for recruitment of oligodendro-
cytes to areas of damage—an essential prerequisite for lesion repair in this devastating
human pathological condition [69] . Interestingly, it has recently been shown that the
levels of HMGB1 correlate with active inflammation lesions of multiple sclerosis and
experimental autoimmune encephalomyelitis [32] . Altogether, these findings suggest
that HMGB1 could be involved in the molecular mechanisms responsible for disease
progression.
Finally, we detected an HMGB1-dependent astrocyte release of the CX 3 CL1
chemokine, the only member of the -chemokine subfamily. CX 3 CL1 is almost
exclusively expressed in the brain, where it plays an important role in neuroinflam-
mation and neurodegeneration [70] . It has been demonstrated previously that this
chemokine is induced in astrocytes within inflammatory lesions and plays a criti-
cal role in neuron-to-glia communication after peripheral nerve injury and inflamma-
tion [71] . A membrane-bound form of this chemokine has been interpreted as a cell
adhesion molecule for circulating inflammatory cells [72] . Conversely, the soluble
form of CX 3 CL1 can create a chemotaxic gradient for natural killer (NK) cells in
the CNS [73] . However, this chemokine plays multiple roles. At low concentration,
it seems to be predominantly involved in cell regulation, survival, and proliferation,
though it also reduces the excitotoxicity caused by excessive neuronal exposure to
glutamate [74] . Hence, it has been proposed that this chemokine can play a general
physiological function and can behave as an anti-inflammatory mediator. Following
the identification of a proteinase involved in the cleavage of CX 3 CL1 from the cell
membrane, it has been postulated that the regulation of this cleavage may affect the
biological functions of this chemokine. The present finding, showing that HMGB1
induces astrocytes to express and release CX 3 CL1, is consistent with a very complex
role played by this cytokine in the CNS, as a modulator of cell mechanisms underly-
ing both neurodegenerative and protective functions.
The release of CXC and CX 3 C chemokines was markedly reduced by PD098059,
providing further evidence that the MAPK/ERK1/2 cascade is a fundamental media-
tor in the astrocyte activation program promoted by HMGB1 signaling. It has been
shown previously that reactive astrocytes, in response to inflammatory agents, are
able to secrete a set of extracellular matrix-degrading enzymes that include the matrix
metalloproteinases [75,76] . Increased MMP proteolytic activity contributes to the
pathogenesis of many neuroinflammatory and neurodegenerative conditions in the
CNS. Early and late induction of different MMPs has been proposed to play a role in
neuronal death as well as in repair processes following hypoxia-ischemia insults [77] .
Zymography analysis ( Figure 3.7(A) ) revealed that the conditioned media of astro-
cytes subjected to stimulation with HMGB1 for 24 hours contained increased amounts
of MMP-9. The proteinase was released in an HMGB1-dose-dependent manner and
again, this cell response to HMGB1 was prevented by PD098059 ( Figure 3.7(B) ).
In contrast, MMP-2 was not modulated by HMGB1, and the MEK inhibitor
PD098059 did not affect the release of this metalloproteinase. The ability of HMGB1
to induce MMP-9 release further supports the idea that HMGB1 displays signaling
properties quite different from those typical of classical inflammatory agents such
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