Abstract: TH-PO0246
Myeloid TLR4 Signaling Promotes the AKI-to-CKD Transition by Inducing Trained Immunity
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Ruan, Yuyi, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Yiu, Wai Han, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Lam, Derek Kong, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Ma, Jingyuan, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Du, Yujun, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Liu, Dan, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Luo, Xu, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Lai, Kar Neng, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Tang, Sydney, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
Background
Acute kidney injury (AKI) is a pivotal risk factor for progression to chronic kidney disease (CKD). This transition is closely associated with chronic inflammation, particularly involving infiltrating macrophages that develop “trained immunity” - an innate immune memory that triggers heightened responses to secondary insults. Growing evidence shows that trained immunity is a key driver of maladaptive repair in various chronic inflammatory disorders. Although Toll-like receptor 4 (TLR4) is known to regulate trained immunity in macrophages, its role in governing AKI-to-CKD transition remains unexplored.
Methods
A mouse model of folic acid-induced nephropathy (FAN) was established using myeloid-specific TLR4 knockout (TLR4flox/flox-LysM-Cre; KO) and TLR4 wild type (TLR4flox/flox; WT) mice. Bone marrow-derived macrophages (BMDMs) were isolated from TLR4 WT and KO mice from FAN and control groups to determine the role of TLR4 on AKI-induced trained immunity, including inflammatory gene expression by real-time qPCR, metabolic changes in oxidative phosphorylation using Seahorse XFe96, and alterations in chromatin accessibility via ATAC-sequencing.
Results
Myeloid-specific TLR4 KO mice with FAN exhibited an improvement in kidney function, reduced kidney inflammation and fibrosis compared to WT group. BMDMs isolated from WT mice with FAN showed a significant increase in IL-4/IL-13-induced Arg-1 expression and LPS/IFN-γ-induced IL-1β expression compared with WT mice in control group. In contrast, TLR4 deficiency in BMDMs from FAN blunted these exaggerated immune responses to secondary stimulation. Furthermore, BMDMs from WT post-AKI mice displayed gene upregulation of key glycolytic enzymes (HK2 and PFK1) and downregulation of mitochondrial oxygen consumption rate (OCR). ATAC-seq revealed a significant difference in chromatin accessibility between BMDMs from WT and TLR4 KO mice. KEGG analysis highlighted genes associated with differentially accessible regions were enriched in several biological pathways including “Lysine degradation”, “Th17 cell differentiation”, and “Motor Proteins”.
Conclusion
AKI induces TLR4-mediated trained immunity in myeloid cells through chromatin remodeling, and metabolic reprogramming, leading to hyper-responsive immune reactions and persistent kidney inflammation. Targeting TLR4-trained immunity axis may provide a new therapeutic approach to retard or prevent AKI-to-CKD progression.
Acknowledgment
Research Grants Council of Hong Kong (General Research Fund, grant no. 17123525) and Hong Kong Society of Nephrology Research Grant (2024)