Review decodes PI3K/Akt/mTOR and JAK/STAT signaling crosstalk in Multiple Sclerosis neuroinflammation

Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder marked by demyelination, axonal injury, and progressive neurological dysfunction. Current therapies primarily target adaptive immune cells, often falling short in addressing the complex neuroinflammation and neurodegeneration. Understanding the precise molecular mechanisms driving disease progression, particularly the interconnected signaling networks like PI3K/Akt/mTOR and JAK/STAT, is crucial for developing more effective, targeted interventions beyond broad immunosuppression.

This comprehensive review synthesized current preclinical and clinical literature to critically examine the mechanistic crosstalk between the PI3K/Akt/mTOR and JAK/STAT signaling pathways in Multiple Sclerosis pathology. The authors analyzed their contributions to neuroinflammation, immune dysregulation, and disease progression. The review specifically highlighted the context-dependent roles of these pathways across various cell types, including immune cells, neurons, glia, endothelial cells, and oligodendrocyte precursor cells, to identify novel therapeutic opportunities and challenges.

The review revealed that dysregulated PI3K/Akt/mTOR signaling significantly influences T-cell activation, immunometabolic reprogramming, autophagy, and oligodendrocyte survival in MS. Concurrently, aberrant activation of the JAK2/STAT3 axis promotes Th17-cell differentiation, cytokine amplification, and sustained inflammatory responses within the central nervous system. A critical finding was the convergence between Th17/STAT3 signaling and PI3K/Akt-mediated metabolic pathways, establishing a regulatory network that enhances microglial activation, blood-brain barrier disruption, and neuronal injury. The review also underscored the dual role of mTOR signaling, which can support remyelination and oligodendrocyte maturation while also contributing to neurodegeneration when excessively activated. Pharmacological modulation of these pathways has shown promise in preclinical and clinical settings, attenuating inflammatory responses and improving neuroprotection. However, therapeutic translation faces challenges due to their essential physiological functions.

The intricate crosstalk between PI3K/Akt/mTOR and JAK/STAT pathways drives key aspects of MS pathology, from immune cell activation to neurodegeneration.