Abstract: PO0156
IRF8-Dependent Regulation of Kidney Dendritic Cells in Ischemic AKI
Session Information
- AKI Mechanisms - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Na, Li, Division of Nephrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Steiger, Stefanie, Division of Nephrology, Department of Medicine IV, Hospital of the LMU Munich, Munich, Germany
- Zheng, Zhihua, Division of Nephrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Anders, Hans J., Division of Nephrology, Department of Medicine IV, Hospital of the LMU Munich, Munich, Germany
- Lichtnekert, Julia, Division of Nephrology, Department of Medicine IV, Hospital of the LMU Munich, Munich, Germany
Background
Ischemic acute tubular necrosis is a common cause of acute kidney injury (AKI), which involves a greater functional diversity of mononuclear phagocytes (MPCs) such as dendritic cells (DCs). The deletion of DCs induce more kidney injury and impair the recovery of AKI. The hematopoietic transcription factor IRF8 mediates the phenotype of DC. However, the role of IRF8 dependent mechanism during AKI is not well known. Hence, we hypothesized that the dynamically altered expression of IRF8 in DCs could contribute to AKI.
Methods
AKI was induced by transient renal pedicle clamping in C57BL6/J. Kidneys, lymph nodes and spleens were collected on D1, D3 and D7. MPCs were identified by Flow cytometry. Expression of IRF8 and MHC II were quantified by IHC. The knockdown of IRF8 was performed by transfecting siRNA in bone marrow-derived DCs (BMDCs). BMDCs were stimulated with necrotic supernatant from tubular epithelial cells or histones and analyzed by phagocytosis assay, T cell differentiation assay, RT-PCR or flow cytometry.
Results
In vivo, we identified four distinct phenotypically MPCs with diverse expression patterns of CD11b/CD11c during post-ischemic AKI. During the late injury and repair phase (D3 and D7), CD11blowCD11chi R4 subsets significantly increased (Figure), which were identified as CD103+ CD11b- DCs with significantly upregulated expression of IRF8. This pattern was consistent in spleen and lymph nodes. In kidney, more IRF8+ cells distributed among the tubulointerstitium and the expression of IRF8 increased significantly during D3 and D7. Further, IRF8+ cells showed co-staining with MHCII. In vitro, IRF8 knockdown in BMDCs induced a significant downregulated CD8a+ CD11b- cells and expression of IL-22 upon necrotic supernatant or histone stimulation. Furthermore, IRF8 knockdown significantly reduced DCs maturation, phagocytosis capacity and naïve T cells polarization.
Conclusion
DC-like MPCs appear in the recovery phase of AKI in a IRF8-dependent mechanism. Selective deletion of IRF8 profoundly alters the phenotype of DCs in response to injury. It implies that selective targeting of IRF8hi DCs may provide an effective strategy to induce immune-modulation of the progression of AKI.
Funding
- Government Support - Non-U.S.