Increased of Fascin1 and Pak1 expression enhances age-associated B cell actin cytoskeleton remodeling

Abstract

Background: An atypical B cell subset of age-associated B cells (ABCs) accumulate with age in mice and humans. ABCs acquire the ability to secrete antibodies and inflammatory cytokines in response to TLR7 and TLR9, and present antigens to T cells more efficiently than follicular (FO) B cells, which promotes the development of pathogenic phenotypes in aged individuals. Results:In this study, we demonstrated that actin cytoskeleton remodeling is enhanced in ABCs compared to FO B cells. ABCs showed higher motility across Transwell membranes and 3-dimensional (3D) collagen gels, without chemoattractants. Due to chemokine receptor expression remodeling, 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. In the presence of a Pak1 inhibitor, IPA3, migration of ABCs in both Transwell chambers and 3D-collagen gels was significantly attenuated. In contrast, a Fascin1 inhibitor, migrastatin, only reduced ABC migration in the 3D collagen gel. The ability to present antigens to T cells was also enhanced in ABCs, in which the Fascin1 mediated pathway is implicated. Conclusion: Increased expression of Fascin1 and Pak1 enhances actin cytoskeleton remodeling in ABCs, promoting motility and antigen presentation. With these phenotypes, ABCs efficiently uptake and present antigens to T cells, and disperse easily within secondary lymphoid tissues.