2. Academic Validation
  3. The TGFB1-Wnt/β-catenin axis programs a neuroprotective IGF1+ microglial state during epileptogenesis

The TGFB1-Wnt/β-catenin axis programs a neuroprotective IGF1+ microglial state during epileptogenesis

  • Int Immunopharmacol. 2026 Jun 1:178:116579. doi: 10.1016/j.intimp.2026.116579.
Ziwei Yuan 1,  Yan Liu 1,  Ran Duan 1,  Xiaogang Zhang 2,  Liqin Hu 3,  Fei Song 4,  Jing Liu 5,  Yuan Meng 1,  Pingyang Ke 1,  Fei Xiao 6
Affiliations

Affiliations

  • 1 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Rare Disease, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 2 Department of Neurology, Chongqing General Hospital, Chongqing University, Chongqing Key Laboratory of Neurodegenerative Diseases, No.118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China.
  • 3 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Rare Disease, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, School of BioMedical Sciences, Hunan University, Changsha, China.
  • 4 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Rare Disease, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Cardiology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400011, China.
  • 5 Department of Neurology, Chongqing University Three Gorges Hospital, 165 Xincheng Road, Chongqing 404100, China.
  • 6 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Rare Disease, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
PMID: 41911647 DOI: 10.1016/j.intimp.2026.116579
Abstract

Temporal lobe epilepsy (TLE) remains a major clinical challenge, with over one-third of patients resistant to existing medications. Microglia, the brain's resident immune cells, are highly plastic, yet their potential to adopt a protective state in epilepsy is unclear. Using time-resolved single-nucleus RNA Sequencing (snRNA-seq) in a kainic acid (KA)-induced seizure model, we identified an early-emerging microglial subpopulation transcriptionally distinct from homeostatic microglia. This subpopulation was characterized by high expression of insulin-like growth factor 1 (Igf1), along with Myo1e and Apbb2. Through in vitro co-culture assays, we demonstrated that TGFB1 stimulation, but not LPS, drives the generation of this IGF1+ phenotype. These induced IGF1+ microglia significantly suppressed the secretion of pro-inflammatory cytokines under inflammatory conditions. Importantly, conditioned medium from IGF1+ microglia enhanced the proliferation and survival of KA-exposed HT22 neuronal-like cells. Mechanistically, we found that TGFB1 activates the Wnt/β-catenin pathway, promoting the nuclear translocation of β-catenin, which in turn upregulates IGF1 expression. In vitro, we abolished the TGFB1-induced neuroprotective phenotype by knocking down β-catenin using siRNA; however, exogenous supplementation with IGF1 partially rescued this effect. Our findings define a TGFB1-β-catenin-IGF1 axis that drives microglia into a neuroprotective state, revealing a novel endogenous mechanism and therapeutic direction for epilepsy.

Keywords

Epilepsy; IGF1; Microglia; Neuroprotection; snRNA-seq.

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