IL-33-induced neuroimmune regulation in depression: A narrative review from molecular mechanisms to therapeutic potential

Depression is a common mental illness characterized by significant variability in treatment response and resistance to current antidepressant drugs and psychotherapy. Recent advances in neuroimmunology have highlighted the immune system's crucial role in the pathogenesis of depression. This review explores the dual roles of interleukin-33 (IL-33) in neuroimmune regulation, neuroinflammation, and neuroplasticity, aiming to investigate its potential as a therapeutic target for depression. An integrative review of the literature was conducted, focusing on the molecular mechanisms of IL-33 in neuroinflammation and its impact on microglia, astrocytes, and the hypothalamic-pituitary-adrenal axis. Animal model studies and clinical evidence regarding IL-33 levels in depression were also analyzed. IL-33 exhibits both pro-inflammatory and anti-inflammatory functions and regulates key immune cells in the central nervous system, including microglia and astrocytes. It regulates neuroinflammation and improves neural plasticity, which is often impaired in depression. Clinical studies show decreased IL-33 levels in the blood and cerebrospinal fluid of depression patients, correlating with disease severity. IL-33 holds promise as a potential biomarker for depression and may serve as a therapeutic target. Recent therapeutic strategies targeting its receptor (suppression of tumorigenicity 2) and signaling pathways are under investigation, with early clinical trials focusing on anti-IL-33 receptor antibodies and signaling pathway inhibitors. However, challenges remain regarding immune-related side effects, and further clinical studies are needed to ensure the safety and efficacy of IL-33-targeted therapies.