Abstract Details

Title Central Effects of BTK Inhibition in Neuroinflammation

Topic Multiple Sclerosis

Presentation(s) S49 - Multiple Sclerosis: Basic Science (1:24 PM-1:36 PM)

Poster/Presentation
Number 003

Objective To assess the role of Bruton’s tyrosine kinase (BTK) signaling in modulating inflammatory processes in microglial cells in vitro and in vivo.

Background Innate immune activation in the central nervous system (CNS) has been proposed to be a key driver of disease progression in multiple sclerosis (MS). BTK is expressed in B cells and innate immune cells, including macrophages and microglia. In B cells, this kinase is an essential component of the B-cell receptor signaling pathway regulating proliferation, maturation, antigen presentation, and production of secreted immunoglobulins. We hypothesize that in addition to its role in B cells, BTK regulates microglial deleterious inflammatory signaling; therefore, inhibiting BTK with a brain-penetrant inhibitor may provide therapeutic benefit within the CNS by targeting innate immunity associated with disease progression in MS.

Design/Methods RNA sequencing, immunohistochemistry, and Western blotting were used to measure BTK or phospho-BTK in primary mouse microglial cell lines, mouse brains, or postmortem human MS brains.

Results We demonstrated basal activity of BTK in murine microglial cells in vitro that was enhanced by stimulation with immune complexes and silenced with a BTK inhibitor. Transcriptome analysis was used to generate a microglial gene expression signature of BTK signaling, identifying unique RNA biomarkers of BTK activation or inhibition. This novel BTK-dependent transcriptional profile was confirmed in vivo, using direct stereotaxic injection of aggregated IgG to mouse brain. Oral administration of a brain-penetrant BTK inhibitor downregulated the BTK-dependent gene expression signature in mouse brain. In tissue derived from autopsy specimens, immunohistochemistry studies coupled with single-nucleus RNA sequencing demonstrated that BTK was expressed in B cells as well as in microglial cells, with increased levels in MS lesion samples.

Conclusions BTK-dependent inflammatory signaling in microglia can be modulated using brain-penetrant BTK inhibitors, which could abrogate microglia-driven neuroinflammation implicated in disease progression in MS.

Authors/Disclosures
Ross C. Gruber, PhD (Takeda) PRESENTER	Dr. Gruber has received personal compensation for serving as an employee of Sanofi. Dr. Gruber has received stock or an ownership interest from Sanofi.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Evis Havari, Msc (Sanofi)	Ms. Havari has received personal compensation for serving as an employee of sanofi.
Tarek Samad, PhD (Sanofi)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Bruce D. Trapp, PhD (Cleveland Clinic)	Dr. Trapp has received personal compensation for serving as an employee of Renovo Neural Inc.. The institution of Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Therini Bio, Inc.. Dr. Trapp has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Trapp has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Disarm Therapeutics. Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Kantonsspital Aarau AG. Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for triMS.online. The institution of Dr. Trapp has received research support from Genzyme Corporation. The institution of Dr. Trapp has received research support from ALS Association. The institution of Dr. Trapp has received research support from National Institute of Neurological Disorders and Stroke.
	No disclosure on file

��ɫ��

��ɫ��