Chemotherapy-induced
peripheral neuropathy (CIPN) impacts a growing number of cancer survivors and treatment options are limited.
Histone deacetylase 6 (HDAC6) inhibitors are attractive candidates because they reverse established CIPN and may enhance anti-
tumor effects of
chemotherapy. Before considering clinical application of HDAC6 inhibitors, the mechanisms underlying reversal of CIPN need to be identified. We showed previously that deletion of Hdac6 from sensory neurons did not prevent
cisplatin-induced mechanical
hypersensitivity, while global deletion of Hdac6 was protective, indicating involvement of HDAC6 in other cell types. Here we show that local depletion of MRC1 (CD206)-positive macrophages without affecting microglia by intrathecal administration of mannosylated
clodronate liposomes reduced the capacity of an HDAC6 inhibitor to reverse
cisplatin-induced mechanical
hypersensitivity. The HDAC6 inhibitor increased spinal cord
Il10 mRNA and this was M2-macrophage dependent. Intrathecal administration of anti-IL-10 antibody or genetic deletion of
Il10 prevented resolution of mechanical
hypersensitivity. Genetic deletion of the
IL-10 receptor from Advillin+ neurons prevented resolution of mechanical
hypersensitivity in mice treated with the HDAC6 inhibitor. These findings indicate that treatment with an HDAC6 inhibitor increases macrophage-derived
IL-10 signaling to
IL-10 receptors on Advillin+ sensory neurons to resolve mechanical
hypersensitivity.
Cisplatin decreases mitochondrial function in sensory axons, and HDAC6 inhibition can promote axonal transport of healthy mitochondria. Indeed, the HDAC6 inhibitor normalized
cisplatin-induced tibial nerve mitochondrial deficits. However, this was independent of macrophages and
IL-10 signaling. In conclusion, our findings indicate that administration of an HDAC6 inhibitor reverses
cisplatin-induced mechanical
hypersensitivity through two complementary pathways: macrophage HDAC6 inhibition to promote
IL-10 production and
IL-10 signaling to DRG neurons, and neuronal HDAC6 inhibition to restore axonal mitochondrial health.