Background/Purpose: NFAT5, a well known osmo-protective factor, can be activated by isotonic stimuli, such as Toll-like receptor (TLR) triggering. Here, we identified a novel signal pathway activated in macrophages upon TLR ligation.

Methods: We demonstrated that high salt and TLR ligation activate distinct sets of downstream target genes in a NFAT5-dependent manner. While ROS are essential for this, their source differs depending on the context; mitochondria for high salt and xanthine oxidase for TLR. The two pathways are mutually suppressive. Moreover, the xanthine oxidase-NFAT5 pathway is required for TLR-mediated inflammatory arthritis, inducing the proinflammatory cytokine production. 

Results: we identified a novel xanthine oxidase- reactive oxygen species (ROS)-p38-NFAT5 pathway activated in macrophages upon TLR ligation.

Conclusion: Together, xanthine oxidase-derived ROS function as molecular sensors to discriminate TLR ligation from osmotic stimulus in macrophages, directing NFAT5 action toward innate immunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/xanthine-oxidase-derived-ros-direct-context-dependent-action-of-nfat5-toward-inflammatory-response-in-macrophages/