Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

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dc.contributor.authorLanglois, Julie
dc.contributor.authorLange, Simona
dc.contributor.authorEbeling, Martin
dc.contributor.authorMacnair, Will
dc.contributor.authorSchmucki, Roland
dc.contributor.authorLi, Cenxiao
dc.contributor.authorDeGeer, Jonathan
dc.contributor.authorSudharshan, Tania J. J.
dc.contributor.authorYong, V. W.
dc.contributor.authorShen, Yun-An
dc.contributor.authorHarp, Christopher
dc.contributor.authorCollin, Ludovic
dc.contributor.authorKeaney, James
dc.date.accessioned2024-11-03T01:04:41Z
dc.date.available2024-11-03T01:04:41Z
dc.date.issued2024-10-27
dc.date.updated2024-11-03T01:04:41Z
dc.description.abstractAbstract Background Bruton’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. Methods Here 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. Results We 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. Conclusions Our 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.
dc.identifier.citationJournal of Neuroinflammation. 2024 Oct 27;21(1):276
dc.identifier.urihttps://doi.org/10.1186/s12974-024-03267-5
dc.identifier.urihttps://hdl.handle.net/1880/120039
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleFenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways
dc.typeJournal Article
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