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However, a fuller understanding of the physiological role of secreted HMGB1 in cell-to-cell interactions requires an experimental strategy using in vivo models. In addition to its role in the nucleus, HMGB1 is reported to be secreted via both active and passive pathways: passively via burst release from necrotic cells, and actively from myeloid lineage cells in response to various stimuli, such as endotoxin, tumor necrosis factor alpha (TNFα), and reactive oxygen species (ROS). In the nucleus, HMGB1 acts to sustain nucleosome formation, chromosomal stability, DNA repair, and telomere maintenance through a cell-autonomous mechanism. High-mobility group box 1 (HMGB1) is a nonhistone DNA-binding nuclear protein. Collectively, our results suggest that an increase of HMGB1, released from astrocytes, upregulates TH expression in an acute MPTP-induced Parkinsonian mouse model, thereby maintaining dopaminergic neuronal functions. Moreover, stereotaxic injection of recombinant HMGB1 attenuated the MPTP-induced reduction of TH in a Parkinsonian mouse model. In addition, MPTP induced a decrease in TH expression, an effect that was potentiated by inhibition of c-Jun N-terminal kinase (JNK) or RAGE.

HMGB1 was predominantly localized to astrocytes and may affect neighboring dopaminergic neurons in the MPTP mouse model, owing to co-localization of RAGE in these TH-positive cells. Here, using immunohistochemistry, we show that HMGB1 and RAGE expression are higher in the nigral area of MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a toxin-induced Parkinsonian mouse model, compared with saline-treated controls. The HMGB1-RAGE (receptor for advanced glycation end products) axis upregulates tyrosine hydroxylase (TH) expression in response to extracellular insults in dopaminergic neurons in vitro, but little is known about HMGB1 in modulation of dopaminergic neurons in vivo. High-mobility group box 1 (HMGB1) is actively secreted from inflammatory cells and acts via a non-cell-autonomous mechanism to play an important role in mediating cell proliferation and migration.