Mucosal TLR5 activation controls healthspan and longevity.

Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.

Caveolin-1 mediates Salmonella invasion via the regulation of SopE-dependent Rac1 activation and actin reorganization.

Caveolar endocytosis has an important function in the cellular uptake of some bacterial toxins, viruses, and circulating proteins. However, the molecular machinery involved in caveolae-dependent bacterial endocytosis is poorly defined. In the present study, we identify a new molecular mechanism for the caveolin-1-dependent entry of Salmonella into host cells via the direct regulation of actin reorganization. In contrast to the interaction of caveolae with other pathogens, the caveolae did not form Salmonella-containing vesicles or endosomes in the host cells. Instead, the caveolae rapidly moved to the apical plasma membrane upon actin condensation during early invasion. Interestingly, the injected bacterial protein SopE interacted with Rac1 to regulate actin reorganization, and both proteins colocalized and directly interacted with caveolin-1 in caveolae during early invasion. After the complete internalization of Salmonella, SopE levels decreased both in the caveolae and in the host cytoplasm; Rac1 activity was also decreased. Downregulation of caveolin-1 by siRNA treatment led to reduction of Salmonella invasion compared with control siRNA-treated cells. These results suggest a new model in which caveolin-1 might be involved in Salmonella entry via its interaction with SopE and Rac1, leading to enhanced membrane ruffling for phagocytosis into host cells.