Kidney Week

Abstract: SA-PO085

Interferon Regulatory Factor 4 (IRF4)-Dependent Type 2 Conventional Dendritic Cells (cDC2s) Promote Kidney Inflammation and Injury in Ischemia-Reperfusion Injury (IRI)-Induced AKI/AKD

Session Information

• AKI: Inflammation and Cell Cycle
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Long, Hao, Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University, Munich, Germany

Hao Long, MD

• Borisova, Kristina Ognianova, Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University, Munich, Germany

Kristina Ognianova Borisova

• Anders, Hans J., Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University, Munich, Germany

Hans J. Anders, MD

• Lichtnekert, Julia, Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University, Munich, Germany

Julia Lichtnekert, MD

Background

Ischemia-reperfusion injury(IRI) is a frequent cause of AKI/AKD.cDCs play pivotal immunoregulatory roles in kidney injury and repair.Previous research had indicated that cDC1s and cDC2s may have opposing roles.We demonstrated a protective function of cDC1s in the IRI-induced AKI/AKD model.In our study,we investigated the functions of cDC2s in AKI/AKD.

Methods

In vivo, we did unilateral IRI on IRF4^fl/flClec9a^cre and WT mice.IRF4 deletion on DC lineage led to a diminished proportion of the cDC2s.We analyzed kidney function,kidney immune cells,i.e.,DC subsets,neutrophil infiltration,T cell differentiation,inflammatory responses.
We differentiated in vitro bone-marrow-derived DCs from IRF8^fl/flClec9a^cre and WT mice using an in-house produced FLT3L supernatant and a recombinant GM-CSF.We compared the phenotype of the generated cells based on the surface markers and essential genes.With different TLR stimulants,we analyzed cytokine secretion,DC activation,migration,and phagocytosis (IHC,IF,ELISA,flow cytometry,transwell migration assay,qPCR).

Results

IRF4 ko mice had a lower proportion of cDC2s in kidney than WT mice.After uIRI,IRF4 ko mice showed reduced renal tubular cell injury,improvement of kidney function and recovery than WT mice.This was associated with increased expression of anti-inflammatory,decreased pro-inflammatory cytokines and acute tubular cell death,reduced recruitment of neutrophils,and differentiation of Th2 and Th17 cells.
In vitro,WT DCs exhibited a cDC1 phenotype,but IRF8 ko cells resulted in the evolution to cDC2. With LPS and CpG stimulations,these cDC2-like cells displayed elevated activation,phagocytic and migration capabilities. Additionally,they exhibited a higher proinflammatory roles,with increased levels of CXCL2 than WT cells.

Conclusion

Our data demonstrated that IRF4 was essential for the differentiation of kidney cDC2s .The reduction of cDC2s ameliorated kidney inflammation,reduced kidney injury, and promoted kidney recovery.
In-vitro IRF4^high cDC2-like cells could be generated by IRF8 deletion in DC lineage cells,which led to a shift in cell fate and an increased proinflammatory phenotype.
Together,cDC2s had an immunoregulatory role in AKI/AKD and could serve as a potential therapeutic target for improving kidney injury and inflammation.