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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 [...]

Despite recent advances in understanding chronic inflammation remission, global analyses have not been explored to systematically discover genes or pathways underlying the resolution dynamics of chronic inflammatory diseases. Here, we performed time-course gene expression profiling of mouse synovial tissues along progression and resolution of collageninduced arthritis (CIA) and identified genes associated with inflammation resolution. Through network analysis of these genes, we predicted 3 key secretory factors responsible for the resolution of CIA: Itgbl, Rps3, and Ywhaz. These factors were predominantly expressed by Tregs and antiinflammatory M2 macrophages, suppressing production of proinflammatory cytokines. In particular, Ywhaz was elevated in the sera of mice with arthritis resolution and in the urine of rheumatoid arthritis (RA) patients with good therapeutic responses. Moreover, adenovirus-mediated transfer of the Ywhaz gene to the affected joints substantially inhibited arthritis progression in mice with CIA and suppressed expression of proinflammatory cytokines in joint tissues, lymph nodes, and spleens, suggesting Ywhaz is an excellent target for RA therapy. Therefore, our comprehensive analysis of dynamic synovial transcriptomes provides previously unidentified antiarthritic genes, Itgbl, Rps3, and Ywhaz, which can serve as molecular markers to predict disease remission, as well as therapeutic targets for chronic inflammatory arthritis., Introduction One of the well-known characteristics of rheumatoid arthritis (RA) is that a large portion of RA patients undergo a clinical course of relapsing-remitting state, rather than experiencing continuous progression [...]

Defective apoptotic death of activated macrophages has been implicated in the pathogenesis of rheumatoid arthritis (RA). However, the molecular signatures defining apoptotic resistance of RA macrophages are not fully understood. Here, global transcriptome profiling of RA macrophages revealed that the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) critically regulates diverse pathologic processes in synovial macrophages including the cell cycle, apoptosis, and proliferation. Transcriptomic analysis of NFAT5-deficient macrophages revealed the molecular networks defining cell survival and proliferation. Proinflammatory M1-polarizing stimuli and hypoxic conditions were responsible for enhanced NFAT5 expression in RA macrophages. An in vitro functional study demonstrated that NFAT5-deficient macrophages were more susceptible to apoptotic death. Specifically, CCL2 secretion in an NFAT5-dependent fashion bestowed apoptotic resistance to RA macrophages in vitro. Injection of recombinant CCL2 into one of the affected joints of [Nfat5.sup.+/-] mice increased joint destruction and macrophage infiltration, demonstrating the essential role of the NFAT5/CCL2 axis in arthritis progression in vivo. Moreover, after intra-articular injection, NFAT5-deficient macrophages were more susceptible to apoptosis and less efficient at promoting joint destruction than were NFAT5-sufficient macrophages. Thus, NFAT5 regulates macrophage survival by inducing CCL2 secretion. Our results provide evidence that NFAT5 expression in macrophages enhances chronic arthritis by conferring apoptotic resistance to activated macrophages., Introduction Nuclear factor of activated T cells 5 (NFAT5) is a member of the Rel family of transcription factors (TFs) that shares a conserved DNA-binding domain with NFATc1-4 and NF-[kappa]B. [...]

Not only are many Mycobacteria pathogens, but they can act as strong non‐specific immunopotentiators, generating beneficial effects on the pathogenesis of some diseases. However, there has been no direct evidence of the effect of mycobacterial species on colorectal cancer (CRC). Herein, we showed that there may be a meaningful inverse correlation between the incidence of tuberculosis and CRC based on global statistics and that heat‐killed Mycobacterial tuberculosis and live Mycobacterium bovis (Bacillus Calmette–Guérin strain) could ameliorate CRC development. In particular, using a faecal microbiota transplantation and a comparison between separate housing and cohousing, we demonstrated that the gut microbiota is involved in the protective effects. The microbial alterations can be elucidated by the modulation of antimicrobial activities including those of the Reg3 family genes. Furthermore, interleukin‐22 production by T helper cells contributed to the anti‐inflammatory activity of Mycobacteria. Our results revealed a novel role of Mycobacteria involving gut microbial alterations in dampening inflammation‐associated CRC and an immunological mechanism underlying the interaction between microbes and host immunity. [ABSTRACT FROM AUTHOR]