2. Academic Validation
  3. TLR9 decreases FOXO3 expression to prevent excessive inflammation in macrophage activation syndrome

TLR9 decreases FOXO3 expression to prevent excessive inflammation in macrophage activation syndrome

  • iScience. 2025 Nov 17;28(12):114098. doi: 10.1016/j.isci.2025.114098.
Mengyan Wang 1,  Yuning Ma 1,  Jianfen Meng 1,  Chengde Yang 1,  Dehao Zhu 1,  Xia Chen 1,  Longfang Chen 1,  Yu Xiao 1,  Da Yi 1,  Hui Shi 1,  Yue Sun 1,  Honglei Liu 1,  Xiaobing Cheng 1,  Yutong Su 1,  Junna Ye 1,  Huihui Chi 1,  Zhuochao Zhou 1,  Tingting Liu 1,  Fan Wang 1,  Jialin Teng 1,  Ping Hu 2 3,  Jinchao Jia 1,  Qiongyi Hu 1
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Guangzhou Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuan Road, Guangzhou 510005, China.
  • 3 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510005, China.
PMID: 41438053 DOI: 10.1016/j.isci.2025.114098
Abstract

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 in vitro, through transcriptional regulation and phosphorylation by Akt. Depletion of Foxo3 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.

Keywords

biochemistry; cell biology; immunology.

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