The Role of the IL-33/ST2 Axis in Nervous System Development and Diseases

Abstract

Interleukin (IL)-33, a cytokine belonging to the IL-1 family, is produced in various tissues, including the nervous system. As a nuclear-stored alarmin protein, IL-33 is released under cell stress or damage, triggering immune responses through its receptor complex, composed of ST2L and the IL-1 receptor accessory protein (IL-1RAcP). The receptors for IL-33 are expressed in various cell types within the nervous system, including neurons, astrocytes, and microglia, and play a crucial role in neurodevelopment and the pathogenesis of neurological diseases. In neurodevelopment, IL-33 promotes microglial metabolic adaptation and phagocytosis via the IL-33/ST2/Akt axis, modulates glial function to affect neural circuit maturation, and influences oligodendrocyte differentiation. In neurological disorders, IL-33 exerts context-dependent regulatory effects in the nervous system through modulation of myeloid and T-cell responses, maintenance of barrier integrity, promotion of tissue repair, and regulation of neuroimmune homeostasis. In acute CNS injuries such as ischemic stroke and traumatic brain injury, IL-33 is generally associated with anti-inflammatory polarization and enhanced repair, although circulating levels may also reflect injury severity. In chronic neurodegenerative diseases including Alzheimer's and Parkinson's disease, IL-33 is implicated in amyloid-β clearance, remyelination, glymphatic function, and neuroprotection, while dysregulation of the IL-33/sST2 axis correlates with disease progression. In contrast, IL-33 may facilitate tumor progression in glioma. Emerging evidence also supports IL-33 and sST2 as potential biomarkers for diagnosis and prognosis in CNS disorders.