ArticleJournal of neuroinflammation2024
Fenebrutinib, a Bruton's tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways.
Article in Journal of neuroinflammation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Fenebrutinib and Effect on the QT/QTc Interval in Healthy Participants.Clinical and translational science · 2026Trial
- Emerging therapeutic strategies in multiple sclerosis: a focus on innovative and targeted approaches.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- The Myelin-Derived Peptide NSDP1 Suppresses Neuroinflammation and Attenuates Demyelination in Chronic Cuprizone-Fed Mice via Modulation of cGAS-STING Signaling.Neurochemical research · 2026Article
- BTK promotes neuroinflammation after intracerebral hemorrhage involving hub genes and alterations in microglial functions.Scientific reports · 2026Article
- Investigations of remibrutinib in models pertinent to multiple sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- B-cell abundance in perivascular cuffs associates with local lesion activity in multiple sclerosis.Acta neuropathologica communications · 2026Article
- Cycloastragenol Derivatives Improve Tyrosine Metabolism, Regulate TLR4/NF-κB/TERT Signaling Pathways, and Inhibit MPTP Induced Neuroinflammation and PD Symptoms.CNS neuroscience & therapeutics · 2026Article
- Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury.Nature immunology · 2026Article
- Sunitinib attenuates secondary injury via the regulation of peri-hematomal microglia at the acute phase of intracerebral hemorrhage.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Bruton Tyrosine Kinase Inhibition Limits Multiple Sclerosis Disease-Driving Inflammation While Promoting Regulatory B Cells.Neurology(R) neuroimmunology & neuroinflammation · 2026Article
- Translational molecular imaging and drug development in multiple sclerosis.Theranostics · 2026Review
- Bruton Tyrosine Kinase in Lesions of Multiple Sclerosis and 3 of Its Models.Neurology(R) neuroimmunology & neuroinflammation · 2025Article
- Update on novel multiple sclerosis treatments: from dismal defeat to scintillating success.Current opinion in neurology · 2025Review
- From diagnosis to treatment: exploring the mechanisms underlying optic neuritis in multiple sclerosis.Journal of translational medicine · 2025Review
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13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundBruton's tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B-lymphocyte and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, BTK inhibitors have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain-penetrant, small-molecule BTK inhibitors may also address compartmentalized neuroinflammation, which is proposed to underlie MS disease progression. BTK is expressed by microglia, which are the resident innate immune cells of the brain; however, the precise roles of microglial BTK and impact of BTK inhibitors on microglial functions are still being elucidated. Research on the effects of BTK inhibitors has been limited to rodent disease models. This is the first study reporting effects in human microglia.
methodsHere we characterize the pharmacological and functional properties of fenebrutinib, a potent, highly selective, noncovalent, reversible, brain-penetrant BTK inhibitor, in human microglia and complex human brain cell systems, including brain organoids.
resultsWe find that fenebrutinib blocks the deleterious effects of microglial Fc gamma receptor (FcγR) activation, including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by fenebrutinib treatment. In contrast, fenebrutinib had no significant impact on human microglial pathways linked to Toll-like receptor 4 (TLR4) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) signaling or myelin phagocytosis.
conclusionsOur study enhances the understanding of BTK functions in human microglial signaling that are relevant to MS pathogenesis and suggests that fenebrutinib could attenuate detrimental microglial activity associated with FcγR activation in people with MS.
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