IL-6 knockout reduces doxorubicin-induced neurotoxicity

Motivation: Doxorubicin (DXR) is a widely used chemotherapy agent associated with inflammation and neurocognitive impairment in cancer survivors. Given that DXR has limited access to the brain, indirect mechanisms, such as the generation of systemic pro-inflammatory cytokines, are proposed to induce neurotoxicity and neuroinflammation. Goal(s): This study aims to probe this hypothesized pro-inflammatory pathway of DXR-induced neurotoxicity. Approach: We identified an elevation of the pro-inflammatory cytokine IL-6 in DXR-treated mice. Consequently, we utilized MRI to assess neuroanatomical changes after DXR treatment in wildtype and Il-6 knockout mice. Results: Our findings revealed that Il-6 knockout partially mitigated the neurotoxic effects induced by DXR. Impact: DXR leads to cognitive impairment that diminishes quality of life for cancer survivors. We demonstrated the involvement of IL-6 in the neurotoxic mechanism of DXR, suggesting a strategy for targeting IL-6 to limit neurotoxicity of cancer treatments.