title: The xanthine oxidase-NFAT5 pathway regulates macrophage activation and TLR-induced inflammatory arthritis.
abstract: NFAT5 (nuclear factor of activated T cells), a well-known osmoprotective factor, can be activated by isotonic stimuli such as Toll-like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO-ROS-p38 MAPK-NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO-derived ROS were selectively required for the TLR-induced NFAT5 activation and NFAT5 binding to the IL-6 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in BALB/c mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL-6 in splenic macrophages in C57BL/6 mice. Collectively, these data support a novel function of the XO-NFAT5 axis in macrophage activation and TLR-induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis.
authors.affiliation: POSTECH-CATHOLIC BioMedical Engineering Institute, The Catholic University of Korea, Seoul, Korea.
authors.forename: Nam-Hoon
authors.initials: NH
authors.lastname: Kim
authors.forename: Susanna
authors.initials: S
authors.lastname: Choi
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Han
authors.forename: Bong-Ki
authors.initials: BK
authors.lastname: Hong
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Choi
authors.forename: H Moo
authors.initials: HM
authors.lastname: Kwon
authors.forename: Sue-Yun
authors.initials: SY
authors.lastname: Hwang
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D014969:Xanthine Oxidase / Q000276:immunology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C118125:NFAT5 protein, human; C492200:Nfat5 protein, mouse; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; D014157:Transcription Factors; D014969:Xanthine Oxidase
keywords: Inflammatory arthritis; Innate immunity; NFAT5; Reactive oxygen species; Xanthine oxidase