Aims. Interleukin-33 is a protein enhancing Th2 cytokine production, initially described as an alarmin that is released from dying, necrotic cells to affect the immune response. Therefore, we aimed to examine the role of IL-33 in response to both CNS and PNS injury. Methods and Results. Using qPCR, Western blotting, and ELISA assay we showed significant up-regulation of IL-33 in two models of nervous system pathology in response to demyelination of the CNS white matter and sciatic nerve crush. We showed that IL-33 is produced exclusively by non-myelinating oligodendrocytes in the intact white matter but neither by their precursors (OPCs) nor mature oligodendrocytes. After CNS white matter demyelination IL-33 is produced by activated OPCs immediately after injury. Using ex vivo organotypic cultures exposed to a demyelination agent we demonstrated secretion of IL-33. On the other hand, Schwann cells, the myelinating cells of PNS, do not produce IL-33 after injury. However, the biological availability of IL-33 is necessary for macrophages to polarize into pro-healing M2 phenotype and support the process of remyelination and regeneration of both, CNS and PNS. Conclusions. Our results show that interleukin-33 is produced and secreted by activated OPCs what shapes the lesion microenvironment by creating pro-regenerative conditions essential to their differentiation. IL-33 could also significantly accelerate peripheral nerve regeneration by attenuating the pro-inflammatory response in the injured tissue. Thus, IL-33 might be a promising target for the diagnostic and therapeutic strategies of demyelinating diseases.This study was supported by the National Science Centre grant 2020/37/B/NZ4/04065