Redox extracellular vesicles induce neurotoxic cytokine production from innate immune cells

Abstract Therapy induced cognition impairment (TICI) or chemobrain is a well-recognized side effect of cancer therapy, which reduces quality of life for cancer survivors. Most cancer therapies induce reactive oxygen species, which can lead to cancer cell death, but they also promote neuronal cell death both directly and indirectly leading to TICI. High grade gliomas are one of the cancers that respond poorly to therapy and are associated with development of chemobrain. Currently, the mechanisms underlying chemobrain are not well understood. The systemic side effects such as cachexia, fatigue, and cognitive impairment are associated with sustained elevation of inflammatory cytokines and microglial cell activation. We tested the hypothesis that chemotherapy and radiation treatment of glioblastoma (GBM) leads to production of extracellular vesicles (EVs) with oxidized proteins that uniquely stimulate specific immune cells to produce cytokines like TNF-α which was shown to induce therapy induced cognition impairment (TICI) by causing neurotoxicity. Previously we showed that TNF-α has a major role in TICI, as it can cross the blood brain barrier and induce neurotoxicity. We found that chemotherapy or radiation induces production of EVs from cells and tissues that are targets of the drugs. These EVs contain more proteins adducted to 4-hydorxy nonenal (HNE) compared to controls. These EVs contain proteins released from tissues such as brain that are damaged by therapy. The HNE adducted EVs were better than control EVs in inducing macrophages and microglial cells to produce the pro-inflammatory cytokines, TNF-α, and IL-6. Serum IL-6 levels and IL-6 producing cells were significantly increased in vivo when C57BL/6 mice were injected with Redox EVs. NIH R01 CA21793