Targeting Neuroinflammation and CNS Repair in MS: From Psychedelics to Oxysterols and Advanced Drug Delivery

Speaker:  Dr hab. Aleksandra Rutkowska 

Medical University of Gdańsk 

Biography of the speaker: 

Aleksandra Rutkowska is a Principal Investigator at the Medical University of Gdańsk and an internationally recognized neuroscientist studying CNS-intrinsic mechanisms of neuroinflammation and remyelination in multiple sclerosis. Her work focuses on immune–brain interactions at the blood–brain barrier, oxysterol signalling pathways, and receptor-mediated regulation of myelin damage and repair. More recently, she has been investigating psychedelic compounds as modulators of neuroinflammation and glial responses, opening new directions for therapeutic strategies in MS and related disorders.  

Description of the general focus of the symposium: 

Neuroinflammation and disrupted lipid signalling are central contributors to pathology in demyelinating and neurodegenerative diseases such as multiple sclerosis (MS). This symposium explores multiple mechanistic domains, including the immunomodulatory effects of serotonergic and sigma-1–active compounds, oxysterol–EBI2 signalling as well as mechanosensitive ion channel Piezo1 and 2 signalling in immune regulation and myelination, and the therapeutic potential of APRIL in modulating acute CNS inflammation. We will also explore lipid-directed transcriptional networks in CNS homeostasis and strategies for targeted drug delivery to the brain. Together, these studies aim to uncover pathways capable of modulating neuroimmune interactions, promoting tissue repair and enhancing therapeutic efficacy in MS. Psychedelic compounds engage 5-HT2A, sigma-1, NMDA, and other receptors involved in neuroimmune regulation. Dimethyltryptamine (DMT) acts as a potent immunomodulator, reducing LPC-induced NF-κB signalling and cytokine release, protecting against demyelination, and suppressing inflammation-driven oligodendrocyte precursor cell (OPC) activation in cerebellar slices. In endothelial cells, DMT counteracts VCAM1 induction and modulates junctional genes, supporting blood–brain barrier integrity.Oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), the endogenous ligand for EBI2 (GPR183), promotes remyelination and regulates lipid metabolism. In cerebellar cultures, 7α,25OHC modulates LXRβ and canonical LXR targets even in EBI2-deficient tissue, while EBI2 activation redistributes lymphocytes, reducing peripheral levels and increasing splenic accumulation. Mechanosensitive Piezo channels influence OPC maturation and myelination, with inhibition protecting against demyelination and activation reducing myelin integrity. Amyloid beta stress in Alzheimer’s disease similarly impairs OPC and oligodendrocyte function, highlighting shared vulnerabilities. AAV-mediated expression of APRIL in cortical neurons mitigates microgliosis and demyelination, activating pathways linked to inflammatory modulation and tissue repair. Importantly, APRIL acts locally to modulate acute CNS inflammation without detectable systemic toxicity, highlighting its therapeutic potential. Collectively, these findings illuminate convergent molecular and physiological mechanisms regulating neuroimmune signalling, lipid metabolism, remyelination, and drug delivery, offering a foundation for the development of next-generation therapeutics for MS. 

Oxysterol-Driven Modulation of Lymphocyte Dynamics Mimics Key Mechanisms of Action of Leading Therapies for Multiple Sclerosis 

Brief description of the talk: 

Oxysterols acting through the EBI2 (GPR183) receptor pathway are emerging as regulators of immune cell trafficking and CNS repair. We investigated the main endogenous EBI2 ligand, oxysterol 7α,25-OHC, and found that its administration markedly reduced circulating lymphocytes while at the same time increasing their accumulation in the spleen, without inducing cell toxicity. This pattern of lymphocyte redistribution resembles key mechanisms shared by several high-efficacy disease-modifying therapies (DMTs) for multiple sclerosis (MS), suggesting that targeting EBI2–oxysterol signalling may represent a therapeutically relevant immunomodulatory axis. Complementary analysis of cerebrospinal fluid and serum from MS patients provide further support for the involvement of oxysterols in the pathophysiology of MS. 

Together, these findings identify oxysterol-mediated modulation of lymphocyte dynamics as a safe and promising immunoregulatory mechanism with potential relevance for MS and other immune-mediated conditions. Ongoing analyses in human samples aim to validate these results and further define their applicability to therapeutic development.