Bruton's Tyrosine Kinase inhibition by Acalabrutinib does not affect early or advanced atherosclerotic plaque size and morphology in Ldlr-/- mice

Hemme, E.: Biskop, D.; Depuydt, M.A.C.; Smit, V.; Delfos, L.; Bernabé Kleijn, M.N.A.; Foks, A.C.; ... ; Bot, I. (2023)

Article / Letter to editor

Atherosclerosis is characterized by the accumulation of lipids and immune cells, including mast cells and B cells, in the arterial wall. Mast cells contribute to atherosclerotic plaque growth and destabilization upon active degranulation. The FcεRI-IgE pathway is the most prominent mast cell activation route. Bruton's Tyrosine Kinase (BTK) is involved in FcεRI-signaling and may be a potential therapeutic target to limit mast cell activation in atherosclerosis. Additionally, BTK is crucial in B cell development and B-cell receptor signaling. In this project, we aimed to assess the effects of BTK inhibition on mast cell activation and B cell development in atherosclerosis. In human carotid artery plaques, we showed that BTK is primarily expressed on mast cells, B cells and myeloid cells. In vitro, BTK inhibitor Acalabrutinib dose-dependently inhibited IgE mediated activation of mouse bone marrow derived mast cells. In vivo, male Ldlr^-/- mice were fed a high-fat diet for eight weeks, during which mice were treated with Acalabrutinib or control solvent. In Acalabrutinib treated mice, B cell maturation was reduced compared to control mice, showing a shift from follicular II towards follicular I B cells. Mast cell numbers and activation status were not affected. Acalabrutinib treatment did not affect atherosclerotic plaque size or morphology. In advanced atherosclerosis, where mice were first fed a high-fat diet for eight weeks before receiving treatment, similar effects were observed. Conclusively, BTK inhibition by Acalabrutinib alone did neither affect either mast cell activation nor early- and advanced atherosclerosis, despite the effects on follicular B cell maturation.

• Atherosclerosis
• Inflammation
• Bruton’s Tyrosine Kinase
• Mast Cell
• B Cell

• All authors: Hemme, E.: Biskop, D.; Depuydt, M.A.C.; Smit, V.; Delfos, L.; Bernabé Kleijn, M.N.A.; Foks, A.C.; Kuiper, J.; Bot, I.
• Date: 2023-04-17
• Journal: Vascular Pharmacology
• Volume: 150
• DOI: doi:10.1016/j.vph.2023.107172