Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy.
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in cancer patients. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we report that paclitaxel administration triggers the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1a (IRE1a) in circulating and dorsal root ganglia-resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced overproduction of mitochondrial-derived reactive oxygen species (ROS) that provoked ER stress and IRE1a hyperactivation in macrophages. This process reprogrammed macrophages towards a highly inflammatory state characterized by IRE1a-dependent production of TNF-a, IL-1ß, PGE2, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1a in leukocytes, or treatment with a selective IRE1a pharmacological inhibitor, prevented dorsal root ganglia neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer was associated with the status of IRE1a activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1a as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in cancer patients receiving paclitaxel. Overall design: To investigate whether paclitaxel might impact the global transcriptomic profile of myeloid cells via IRE1a activation, we performed gene profiling analysis using data obtained from RNA-seq of wild-type (WT) versus IRE1a-deficient (cKO) bone marrow differentiated macrophages exposed to paclitaxel (10 µM, n=4) or vehicle control (Dimethyl sulfoxide; DMSO, n=4) treated for 18 hours.