Increased Fascin1 and Pak1 Expressions Enhance Age-Associated B-Cell Actin Cytoskeleton Remodeling and Motility

Abstract

Age-associated B cells (ABCs), an atypical B-cell subset, tend to accumulate with age in mice and humans. These cells exhibit distinct characteristics, such as the ability to secrete antibodies and inflammatory cytokines upon stimulation of Toll-like receptor 7 (TLR7) and TLR9. Additionally, ABCs have been found to be more efficient in presenting antigens to T cells than follicular (FO) B cells. These features contribute to the development of pathogenic phenotypes in aging individuals. In this study, we demonstrated that actin cytoskeleton remodeling was enhanced in CD11b⁺/CD11c⁺ ABCs compared to CD11b⁻/CD11c⁻ B cells. ABCs exhibited higher motility across Transwell membranes and three-dimensional (3D) collagen gels, even without chemoattractants. Due to the remodeling of chemokine receptor expression, ABCs were attracted by CXCL12 and CCL21 rather than CXCL13. Among F-actin remodeling-related factors, expression levels of Fascin1 and Pak1 were increased in ABCs. Treatment with the Pak1 inhibitor, IPA3, significantly attenuated ABC migration in Transwell chambers and 3D collagen gels. In contrast, the Fascin1 inhibitor, migrastatin, only reduced ABC migration in the 3D collagen gel. The increased expression of Fascin1 and Pak1 enhances actin cytoskeleton remodeling in ABCs, facilitating their dispersion within secondary lymphoid tissues.