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ResearchIn-Press PreviewImmunologyNephrology Open Access | 10.1172/JCI185146

Targeting allograft inflammatory factor-1 reprograms kidney macrophages to enhance repair

Irma Husain,1 Holly Shah,1 Collin Z. Jordan,1 Naveen R. Natesh,2 Olivia K. Fay,3 Yanting Chen,4 Jamie R. Privratsky,4 Hiroki Kitai,1 Tomokazu Souma,5 Shyni Varghese,6 David N. Howell,7 Edward B. Thorp,8 and Xunrong Luo9

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Husain, I. in: JCI | PubMed | Google Scholar |

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

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1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

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1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

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1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

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1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Chen, Y. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

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1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

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1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Souma, T. in: JCI | PubMed | Google Scholar |

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Varghese, S. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Howell, D. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Thorp, E. in: JCI | PubMed | Google Scholar |

1Division of Nephrology, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Engineering, Duke University Pratt School of Engineering, Durham, United States of America

3Department of Pathology, Duke University School of Medicine, Durham, United States of America

4Department of Anaesthesiology, Duke University, Durham, United States of America

5Division of Nephrology, Duke Univeristy School of Medicine, Durham, United States of America

6Department of Biomedical Engineering, Duke University, Durham, United States of America

7Department of Pathology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Northwestern University, Chicago, United States of America

9Division of Nephrology, Duke University, Durham, United States of America

Find articles by Luo, X. in: JCI | PubMed | Google Scholar

Published January 21, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI185146.
Copyright © 2025, Husain et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 21, 2025 - Version history
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Abstract

The role of macrophages remains incompletely understood in kidney injury and repair. Their plasticity offers an opportunity to polarize them towards mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney macrophages augmented their AIF-1 expression after injury. Aif1 genetic deletion led to macrophage polarization towards a reparative phenotype while halting the development of kidney fibrosis. The enhanced repair was mediated by higher levels of anti-inflammatory and pro-regenerative markers leading to a reduction in cell death and increase in proliferation of kidney tubular epithelial cells following ischemic reperfusion injury. Adoptive transfer of Aif1-/- macrophages to Aif1+/+ mice conferred protection against ischemia reperfusion injury. Conversely, depletion of macrophages reversed the tissue-reparative effects in Aif1-/- mice. We further demonstrated an increased expression of AIF-1 in human kidney biopsies from native kidneys with acute kidney injury or chronic kidney disease, as well as in biopsies from kidney allografts undergoing acute or chronic rejection. We conclude that AIF-1 is a macrophage marker of renal inflammation, and its targeting uncouples macrophage reparative functions from profibrotic functions. Thus, therapies inhibiting AIF-1 when ischemic injury is inevitable have the potential to reduce the global burden of kidney disease.

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  • Version 1 (January 21, 2025): In-Press Preview
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