Given our recent evidence for the role of high mobility group box 1 (
HMGB1) in
chemotherapy-induced
peripheral neuropathy (CIPN) in rats, we examined the origin of
HMGB1 and the upstream and downstream mechanisms of
HMGB1 release involved in
paclitaxel-induced neuropathy in mice.
Paclitaxel treatment developed
mechanical allodynia in mice, as assessed by von Frey test, which was prevented by an anti-HMGB1-neutralizing antibody or
thrombomodulin alfa capable of inactivating
HMGB1. RAGE or CXCR4 antagonists,
ethyl pyruvate or
minocycline, known to inhibit
HMGB1 release from macrophages, and liposomal
clodronate, a macrophage depletor, prevented the
paclitaxel-induced
allodynia.
Paclitaxel caused upregulation of RAGE and CXCR4 in the dorsal root ganglia and macrophage accumulation in the sciatic nerve. In macrophage-like RAW264.7 cells,
paclitaxel evoked cytoplasmic translocation of nuclear
HMGB1 followed by its extracellular release, and overexpression of CBP and PCAF,
histone acetyltransferases (HATs), known to cause acetylation and cytoplasmic translocation of
HMGB1, which were suppressed by
ethyl pyruvate,
N-acetyl-l-cysteine, an
anti-oxidant, and
SB203580 and
PDTC, inhibitors of
p38 MAP kinase (p38MAPK) and NF-κB, respectively.
Paclitaxel increased accumulation of
reactive oxygen species (ROS) and phosphorylation of p38MAPK, NF-κB p65 and I-κB in RAW264.7 cells. In mice,
N-acetyl-l-cysteine or
PDTC prevented the
paclitaxel-induced
allodynia. Co-culture of neuron-like NG108-15 cells or stimulation with their
conditioned medium promoted
paclitaxel-induced
HMGB1 release from RAW264.7 cells. Our data indicate that
HMGB1 released from macrophages through the ROS/p38MAPK/NF-κB/HAT pathway participates in the
paclitaxel-induced
peripheral neuropathy in mice, and unveils an emerging therapeutic avenue targeting a neuroimmune crosstalk in CIPN.