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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.

Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern- triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6- and chemokine ligand 2-dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation., Introduction Macrophages play a pivotal role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis (RA), with broad proinflammatory, destructive, and remodeling capabilities (1, 2). Similar to other [...]

A number of single nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) have been associated with daptomycin-resistance (DAP-R) in Staphylococcus aureus. Such SNPs have been found throughout the mprF ORF, although there are clearly preferred hot spots within this gene frequently linked to DAP-R phenotype. These mprF SNPs are often correlated with a gain-in-function phenotype, either in terms of increased production (synthase activity) and/or enhanced translocation (translocase activity) of lysyl-phosphatidylglycerol (L-PG) within its cell membrane. However, it is unclear if multiple hot spot mprF SNPs can accumulate within mprF ORFs and cause additive elevations of DAP minimum inhibitory concentrations (MICs). In this study, we used a previously well-characterized plasmid complementation system in S. aureus Newman ΔmprF mutant to express: (1) single point-mutated forms of mprF ORFs cloned from two DAP-R S. aureus strains (mprFS295L or mprFT345A) and (2) dual point-mutated forms of mprF ORFs simultaneously harboring SNPs in the central bifunctional domain and synthase domain in MprF, respectively (mprFS295L+L826F or mprFT345A+L826F). The current study revealed that, although individual hot spot point mutations within mprF ORF can recapitulate signature DAP-R-associated phenotypes (i.e., increased DAP MICs, enhanced surface positive charge, and increased L-PG synthesis), accumulation of such hot spot point mutations paradoxically caused reduction in these latter three metrics.

The efficient dispersion of single-walled carbon nanotubes (SWCNTs) has been the subject of extensive research over the past decade. Despite these efforts, achieving individually dispersed SWCNTs at high concentrations remains challenging. In this study, we address the limitations associated with conventional methods, such as defect formation, excessive surfactant use, and the use of corrosive solvents. Our novel dispersion method utilizes the spontaneous charging of SWCNTs in a solvated electron system created by dissolving potassium in hexamethyl phosphoramide (HMPA). The resulting charged SWCNTs (c-SWCNTs) can be directly dispersed in the charging medium using only magnetic stirring, leading to defect-free c-SWCNT dispersions with high concentrations of up to 20 mg/mL. The successful dispersion of individual c-SWCNT strands is confirmed by their liquid-crystalline behavior. Importantly, the dispersion medium for c-SWCNTs exhibits no reactivity with metals, polymers, or other organic solvents. This versatility enables a wide range of applications, including electrically conductive free-standing films produced via conventional blade coating, wet-spun fibers, membrane electrodes, thermal composites, and core-shell hybrid microparticles. [ABSTRACT FROM AUTHOR]