Abstract: PUB059
Downregulation of Macrophage TREM2 in CKD Impairs Vascular Calcium Crystal Phagocytosis and Exacerbates TLR4-JNK-Mediated Procalcifying Cytokine Release
Session Information
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Author
- Yang, Chih-Yu, National Yang Ming Chiao Tung University - Yangming Campus, Taipei City, Taiwan
Background
Macrophages, as first-line responders to soft tissue calcification, are central to uremic cardiovascular calcification, though underlying mechanisms are unclear. TREM2, an anti-inflammatory receptor on myeloid cells, may regulate this process. This study investigates its role in vascular calcification under uremic conditions.
Methods
TREM2 expression in circulating macrophages was assessed in CKD patients. To examine its function, we used TREM2-knockout and overexpressing THP-1 macrophages to test responses to hydroxyapatite (HA), the key mineral in uremic vascular calcification. A uremic mouse model was used to compare calcification between Trem2-knockout and wild-type mice.
Results
We found that TREM2 on human macrophages binds HA crystals and promotes phagocytosis. TREM2-knockout cells showed reduced ROS and caspase-1 activity but elevated TLR4/JNK signaling and IL-1β/TNF-α release upon HA exposure, leading to osteogenic transdifferentiation of vascular smooth muscle cells. In contrast, TREM2 overexpression reversed these effects. Consistently, Trem2-knockout uremic mice showed increased vascular calcification, and CKD patients with severe calcification had reduced membrane TREM2 in circulating macrophages.
Conclusion
TREM2 downregulation in CKD impairs macrophage clearance of calcified lesions and increases pro-calcifying cytokines via TLR4/JNK signaling. Enhancing TREM2 may help mitigate uremic vascular calcification.
Graphical abstract. TREM2 on macrophages binds HA crystals and enables phagocytosis. In CKD, reduced TREM2 lowers ROS and caspase-1 but elevates TNF-α and IL-1β via JNK signaling, promoting osteogenic transdifferentiation of vascular smooth muscle cells. Trem2-knockout mice develop more severe vascular calcification, supporting TREM2’s protective role.