Astrocytic interleukin-33 regulates glial fibrillary acidic protein expression and is involved in chemical-induced activation of cortical microglia and neuroinflammation
Astrocytes are the most abundant glial cells in the brain. They not only support neurons but also respond to injury or disease by becoming activated, exhibiting features such as hypertrophy and increased expression of glial fibrillary acidic protein (GFAP). Interleukin-33 (IL-33) has been considered an “alarmin” signal and is primarily produced by astrocytes and oligodendrocytes. Although IL-33 has been shown to regulate oligodendrocyte differentiation, its function in astrocytes remains unclear.
In this study, we observed that stimulation with the pro-inflammatory agent LPS (lipopolysaccharide) increased nuclear IL-33 expression in cortical astrocytes, along with elevated GFAP levels. Using lentiviral-mediated IL-33 knockdown (IL33KD) and overexpression (IL33oe), we demonstrated that IL-33 itself promotes GFAP expression.
Interestingly, in a cuprizone (CPZ)-induced demyelination mouse model, the number of GFAP⁺ astrocytes with nuclear IL-33 in the cortex was increased. However, as shown below, IL-33 knockout (il33KO) mice significantly suppressed CPZ-induced GFAP upregulation (green) and astrocyte hypertrophy.
Furthermore, in long-term CPZ-treated il33KO mice, cortical microglial activation was enhanced, accompanied by neuronal damage and anxiety-like behaviors. Our findings indicate that IL-33 participates in astrocyte activation and plays a role in maintaining cortical inflammatory homeostasis and neuroprotection through regulation of astrocyte responses.
Yu-Chen Zheng (鄭宇辰), Wei-Yu Chen, Chih-Yen Wang, Shun-Fen Tzeng (曾淑芬). Astrocytic Interleukin-33 Deficiency Reduces Glial Fibrillary Acidic Protein Expression and Exacerbates Microglial Activation and Neuronal Damage in a Chemically Induced Inflamed Frontal Cortex. Journal of Neurochemistry. 2025 Dec 05. doi: 10.1111/jnc.70310. Online ahead of print. (https://pubmed.ncbi.nlm.nih.gov/41347267/)