Oligodendrocytes (OLs) are a cell population in the central nervous system (CNS) responsible for producing myelin that wraps a neuronal axon and facilitate the propagation of action potential to generate saltatory conduction along the axon (Hughes and Appel, 2016). These cells are derived from oligodendrocyte precursor cells (OPCs) through a process of conversion(Bergles and Richardson, 2015; Nishiyama et al., 2021). Impairment of OL lineage progression and myelinogenesis is not only a consequence of neurological diseases but also a key feature of their manifestation. One such neurological disease is multiple sclerosis (MS), characterized by profound inflammation in the CNS, resulting in early active white matter demyelination and the development of multiple lesions in various brain regions, including the cortex, thalamus, brain stem, and spinal cord (Dulamea, 2017; Klotz et al., 2023; Steinman, 1996). The other CNS neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and depressive disorders, are also associated with OL dysfunction and severe demyelination as the disease progresses (Carmeli et al., 2013; Nishijima et al., 2012; Nonneman et al., 2014; Papuc and Rejdak, 2020; Zhou et al., 2021). Although the pathogenesis of these diseases is partially understood, there is ongoing intensive investigation to elucidate the detailed mechanisms underlying their onset and progression.

IL-33 was initially identified in endothelial cell nuclei and categorized as a member of the IL-1 family (Cayrol and Girard, 2018). The IL-33 precursor protein comprises an IL-1-like cytokine domain and a nuclear localization sequence containing a homeodomain-like helix-turn-helix with a chromatin-binding motif (Carriere et al., 2007). IL-33 functions as a potent alarmin, triggering inflammation by binding to the ST2 receptor encoded by the IL1RL1 gene and inducing Th2-type immune responses (Chan et al., 2019). We have previously characterized IL-33 as the glioma promoting factor and to foster the formation of a favorable glioma-associated microenvironment, facilitating tumor cell expansion and the expression of cytokines/chemokines (Fang et al., 2014). Moreover, the findings from others also indicated IL-33-triggered immune cell infiltration and recruitment at tumor sites (De Boeck et al., 2020). Astrocytes, an abundant CNS glial population, and OLs are the two major IL-33 expressing cell populations in the CNS (Hu et al., 2021). IL-33 has been shown to play a positive regulator for synapse remodeling in the developing spinal cord and thalamus by promoting microglial engulfment (Vainchtein et al., 2018), and promote the formation of functional excitatory synapses in hippocampal CA1 neurons (Wang et al., 2021). IL-33 from damaged OLs can activate astrocytes and microglia at the lesion site, as well as monocyte infiltration, for functional recovery (Gadani et al., 2015). Moreover, the findings have indicated that IL-33 can regulate the activation of glial cells and infiltrating immune cells, as well as to mediate immune cell polarization, for the suppression of AD syndromes (Saresella et al., 2020; Sun et al., 2021). In addition, IL-33 signaling in OLs might be an important factor for MS development via the inhibition of myelination (Allan et al., 2016).

We have provided evidence to verify OPCs and OLs as the major IL-33 expressing cells in the corpus callosum (Sung et al., 2019). However, the expression and function of IL-33 in OLs within the stressed CNS environment have yet to be elucidated. A copper chelator cuprizone (CPZ), bis-cyclohexanone-oxaldihydrazone, has been widespread used to establish a demyelinating rodent model with the features of human MS (Kipp et al., 2009; Zirngibl et al., 2022). CPZ intoxication has been reported to induce mitochondrial dysfunction, reactive oxygen species (ROS), and the altered activity of antioxidative stress enzymes in the corpus callosum (Acs et al., 2013). CPZ intoxication was able to reduce mitochondrial function and in cultured OLs (Benardais et al., 2013). Accordingly, the in vivo and in vitro stress model of CPZ-induced intrinsic OL damage were used in this study.

MS can manifest not only in adulthood but also in children and adolescents. When MS appears during early life, it poses distinctive challenges in diagnosis and treatment, especially given the aggressive condition throughout the lifetime of the patients (Prajjwal et al., 2023). In association with the function of IL-33 in guiding OPCs towards maturation into mature OLs (Sung et al., 2019), we conducted the in vivo investigations using an juvenile mouse model to examine the expression of IL-33 in OLs in the demyelinating corpus callosum induced by the feeding of an animal diet containing CPZ for 6 weeks or 8 weeks. The juvenile animal model demonstrates vulnerability in OLs and myelin in the corpus callosum when exposed to CPZ intoxication (Pfeifenbring et al., 2015; Wang et al., 2013). Our results reveal that IL-33 expression is downregulated in OLs under these conditions. Furthermore, increased IL-33 expression in cultured OLs can protect them from CPZ-induced reduction in MBP levels and in mature OL morphology. These findings provide valuable insights into the role of IL-33 in protecting OLs and maintaining myelin stability against oxidative stress insults.