sIL-2RA Exacerbates Multiple Sclerosis by Activating Microglia and Upregulating Fc Receptors on Microglia
JINGFEI SHI#, YI DING#, HUI LU*
Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
* Corresponding Author: HUI LU. Email: 
# These authors contributed equally to this work
BIOCELL https://doi.org/10.32604/biocell.2026.073956
Received 29 September 2025; Accepted 12 January 2026; Published online 26 January 2026
Abstract
Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Soluble interleukin-2 receptor alpha (sIL-2Rα) has been implicated in MS pathogenesis, but its mechanisms remain unclear. This study investigates how sIL-2Rα exacerbates MS by modulating microglial activation and antibody-dependent cellular cytotoxicity (ADCC) in an experimental autoimmune encephalomyelitis (EAE) mouse model.
Methods: Female C57BL/6J mice were induced with EAE and treated with sIL-2Rα. Clinical symptoms, histopathology, and molecular changes were analyzed. Microglial activation was assessed via immunohistochemistry, Western blot, and RNA sequencing. In vitro, ADCC-mediated oligodendrocyte injury was evaluated using Fc receptor inhibition and PI3K-Akt pathway blockade.
Results: sIL-2Rα accelerated EAE onset and severity, increasing microglial M1 polarization and CNS inflammation. RNA-seq revealed PI3K-Akt pathway activation, upregulating Fc receptors (FcγR) on microglia, which enhanced ADCC against oligodendrocytes (
p < 0.001). Inhibiting FcγR or PI3K-Akt reduced oligodendrocyte damage.
Conclusion: sIL-2Rα exacerbates MS by activating microglia via the PI3K-Aktaxis, promoting ADCC and demyelination. Targeting this pathway may offer novel therapeutic strategies for MS.
Keywords
Multiple sclerosis; soluble interleukin-2 receptor α; microglial activation; phosphatidylinositol 3-kinase–protein kinase B signaling (PI3K-Akt) signaling pathway; antibody-dependent cellular cytotoxicity
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