ArticleProceedings of the National Academy of Sciences of the United States of America2025
Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed.
- Phosphorylated TYK2 orchestrates the pathogenic program of CD4 + T cells in the development of CNS autoimmunity.Journal of neuroinflammation · 2026Article
- A Narrative Review: Do Systemic Drugs Used in the Treatment of Psoriatic Disease Affect Alzheimer's Disease?Dermatology and therapy · 2026Review
- Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.Journal of medicinal chemistry · 2026Review
- How Genomic and Structural Context Could Shape JAK-STAT Variant Pathogenicity.Twin research and human genetics : the official journal of the International Society for Twin Studies · 2026Article
- Tyrosine kinase 2 inhibitors in the therapy of inflammatory and autoimmune diseases.Pharmacological reports : PR · 2025Review
- TYK2 rs34536443 (P1104A) Variant Suppresses ICAM1-Mediated Inflammation: Insights From Mendelian Randomization and Functional Analyses.Psoriasis (Auckland, N.Z.) · 2025Article
Corrections and comments
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Authors and funding
25 authors.
Funding
Abstract
GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). Impaired TYK2 signaling within the central nervous system (CNS) may impart the protective effects of TYK2 P1104A allele in MS. We deployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light (NfL) was reduced in plasma and cerebral spinal fluid (CSF). Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, we demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.
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Registered trials
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