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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 [...]

Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed singlecell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications., Introduction Diseases of the immune system associated with systemic autoimmunity and autoinflammation can result in significant health burdens, which, in many disorders, include a high risk for life-threatening complications. Inflammatory [...]

IL-1[beta] is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1[beta] contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist ([Il1rn.sup.-/-]), we observed that IL-1[beta] blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial [CD4.sup.+][Foxp3.sup.+] Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both [Il1rn.sup.-/-] Tregs and wild-type Tregs differentiated with IL-1[beta] accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding [RANKL.sup.hi][Foxp3.sup.+] T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1[beta]-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis., Introduction IL-1 is a pleiotropic cytokine that plays a key role in the pathogenesis of inflammatory arthritis, including the highly prevalent disease rheumatoid arthritis (RA) and its less common pediatric [...]

Your senior Labrador Retriever is slightly sore after his daily walk and a bit hesitant to climb up to his favorite spot on the couch. A visit with your veterinarian [...]