TLR9 decreases FOXO3 expression to prevent excessive inflammation in macrophage activation syndrome
Adult-onset Still's disease (AOSD) is characterized by an overwhelming inflammatory response and hyperactivation of monocytes/macrophages, which may cause macrophage activation syndrome (MAS). Here, we demonstrate the forkhead box protein O3 (FOXO3), a transcriptional factor downregulated by interferon, as an important regulator of inflammation in AOSD-MAS. FOXO3 expression is downregulated in monocytes/PBMCs from patients with AOSD, especially in those developing MAS. A negative correlation between FOXO3 expression with disease activity and inflammatory level is identified. FOXO3 downregulation can be induced by TLR9 activation both in the murine MAS model and TLR9 agonist-stimulated macrophages <i>in vitro</i>, through transcriptional regulation and phosphorylation by AKT. Depletion of <i>Foxo3</i> protected mice from hyperinflammatory response and organ damage in MAS, and mechanistically, alleviated NLRP3 inflammasome activation in macrophages. Our study reveals mechanisms of FOXO3 in facilitating AOSD-MAS development and identifies the critical role of FOXO3 in the self-negative regulation of inflammation in AOSD through suppression by TLR9 signaling.
Authors
- Hui Shi (ORCID: https://orcid.org/0000-0002-4229-7290)
- Xiaobing Cheng (ORCID: https://orcid.org/0000-0002-1243-5170)
- Huihui Chi (ORCID: https://orcid.org/0000-0001-9587-1180)
- Dehao Zhu (ORCID: https://orcid.org/0009-0007-2229-1004)
- Jialin Teng (ORCID: https://orcid.org/0000-0003-1016-9064)
- Ping Hu (ORCID: https://orcid.org/0000-0002-7297-8847)
- Jinchao Jia (ORCID: https://orcid.org/0000-0003-1507-8540)
- Longfang Chen (ORCID: https://orcid.org/0000-0003-4546-9120)
- Da Yi
- Jianfen Meng (ORCID: https://orcid.org/0000-0001-8660-1170)
- Qiongyi Hu (ORCID: https://orcid.org/0000-0002-4825-5227)
- Chengde Yang (ORCID: https://orcid.org/0000-0002-3720-634X)
- Junna Ye (ORCID: https://orcid.org/0000-0002-2823-4349)
- Yuning Ma (ORCID: https://orcid.org/0000-0002-4435-1174)
- Yutong Su (ORCID: https://orcid.org/0000-0002-0358-8933)
- Fan Wang (ORCID: https://orcid.org/0000-0001-9806-5037)
- Tingting Liu (ORCID: https://orcid.org/0000-0003-1420-1287)
- Xia Chen (ORCID: https://orcid.org/0000-0002-4863-2707)
- Xiao Yu (ORCID: https://orcid.org/0000-0003-3536-953X)
- Mengyan Wang (ORCID: https://orcid.org/0000-0002-8052-0828)
- Zhuochao Zhou
- Yue Sun (ORCID: https://orcid.org/0009-0009-0481-5593)
Institutions
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Guangzhou Experimental Station (CN)
- Second Affiliated Hospital of Guangzhou Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- iScience
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1016/j.isci.2025.114098
- Primary Topic
- Autoimmune and Inflammatory Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00