Targeting interleukin-20 alleviates paclitaxel-induced peripheral neuropathy

Abstract

The role of immune mediators, including proinflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here, we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel upregulated IL-20 through dysregulated Ca2+ homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca2+ homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.

Neuro-immune interactions in paclitaxel-induced peripheral neuropathy

“…IL-17 is elevated in the spinal cord and cerebrospinal fluid of mice following paclitaxel treatment and IL-17 increases NMDAR activity and suppresses GABA-induced currents in the spinal cord [146]. Blockade of IL-17R antibodies or knockdown of IL-17R reduces paclitaxel-induced pain [146] and the same goes for blockade of IL-20 using monoclonal antibodies [147]. IL-20 activates astrocytes, triggering the production of pro-inflammatory mediators in the DRG, including IL-8 and MCP-1.…”

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy

“…Moreover, the systemic blockade of IL-20 significantly decreased systemic inflammation suppressing the pro-inflammatory cascade activation (TNF-α, IL-1β, and MCP-1) and macrophage recruitment in DRG, correlating the role of neuroimmune system to the pain behavior. The importance of IL-20 was further confirmed by the use of IL-20R1 -/- mice, which were protected from PIPN and peripheral nerve degeneration ( 98 ).…”

“…In addition, also the treatment with minocycline prevented IENF loss as well as the development of mechanical hypersensitivity ( 110 , 111 ) as previously reported for OHP. Moreover, IL-20 expression was increased in footpaw of PTX-treated animals and its inhibition prevented IENF loss caused by PTX, suggesting the role of the neuroinflammatory response in CIPN establishment also at IENF level ( 98 ).…”

“…PTX also induced the recruitment, activation and accumulation of macrophages with a pro-inflammatory M1 phenotype in DRG, leading to pro-inflammatory cytokine and chemokines release that in turn induced DRG and distal nerve ending damage ( 98 , 112 – 114 ).…”

“…Therefore, there is a connection between neuroinflammatory elements and monocyte/macrophage infiltration: it was established that CCL2 attracts pro-inflammatory monocytes/macrophages to the DRG, causing a downstream increase of cytokines ( 101 , 115 ) and M1 monocytes population triggering a pro-inflammatory cascade ( 98 ). On the other hand, despite monocyte chemoattractant CCL2 and CCL3 increased in DRG, Makker and colleagues did not observe any macrophage infiltration ( 20 ).…”