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Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression

Sabine Brandt, Tobias M. Ballhause, Anja Bernhardt, Annika Becker, Delia Salaru, Hien Minh Le-Deffge, Alexander Fehr, Yan Fu, Lars Philipsen, Sonja Djudjaj, Andreas J. Müller, Rafael Kramann, Mahmoud Ibrahim, Robert Geffers, Chris Siebel, Berend Isermann, Florian H. Heidel, Jonathan A. Lindquist and Peter R. Mertens
JASN November 2020, 31 (11) 2589-2608; DOI: https://doi.org/10.1681/ASN.2019121289
Sabine Brandt
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
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Tobias M. Ballhause
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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  • ORCID record for Tobias M. Ballhause
Anja Bernhardt
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
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Annika Becker
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Delia Salaru
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Hien Minh Le-Deffge
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Alexander Fehr
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
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Yan Fu
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
3Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Lars Philipsen
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
3Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Sonja Djudjaj
4Institute of Pathology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
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Andreas J. Müller
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
3Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
5Intravital Microscopy of Infection and Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Rafael Kramann
6Department of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
7Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
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Mahmoud Ibrahim
6Department of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
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Robert Geffers
8Genome Analytics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Chris Siebel
9Department of Discovery Oncology, Genentech, Inc., South San Francisco, California
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Berend Isermann
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
10Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
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Florian H. Heidel
11Department of Hematology and Oncology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
12Department of Internal Medicine II, Hematology and Oncology, Friedrich Schiller University Medical Center, Jena, Germany
13Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
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Jonathan A. Lindquist
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
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Peter R. Mertens
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
2Health Campus Immunology, Infectiology and Inflammation (GCI3), Otto-von-Guericke University, Magdeburg, Germany
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Significance Statement

In patients with CKD, receptor Notch3 is strongly upregulated. Conversely, in experimental kidney disease models, Notch3 deficiency protects from organ damage. To determine whether Notch3 on immune cells or tissue-resident cells participates in the inflammatory response, animals with bone marrow chimerism were generated. These animal strains do not exhibit phenotypic differences in the absence of disease. However, after unilateral ureteral obstruction, distinct alterations in the immune response and organ fibrosis become apparent. Notch3 receptors expressed by immune cells are of relevance for transmigration into tissue; the receptors expressed by resident kidney cells orchestrate organ fibrosis. These events seem to be separable and distinct.

Abstract

Background Kidney injuries that result in chronic inflammation initiate crosstalk between stressed resident cells and infiltrating immune cells. In animal models, whole-body receptor Notch3 deficiency protects from leukocyte infiltration and organ fibrosis. However, the relative contribution of Notch3 expression in tissue versus infiltrating immune cells is unknown.

Methods Chimeric mice deficient for Notch3 in hematopoietic cells and/or resident tissue cells were generated, and kidney fibrosis and inflammation after unilateral ureteral obstruction (UUO) were analyzed. Adoptive transfer of labeled bone marrow–derived cells validated the results in a murine Leishmania ear infection model. In vitro adhesion assays, integrin activation, and extracellular matrix production were analyzed.

Results Fibrosis follows UUO, but inflammatory cell infiltration mostly depends upon Notch3 expression in hematopoietic cells, which coincides with an enhanced proinflammatory milieu (e.g., CCL2 and CCL5 upregulation). Notch3 expression on CD45+ leukocytes plays a prominent role in efficient cell transmigration. Functionally, leukocyte adhesion and integrin activation are abrogated in the absence of receptor Notch3. Chimeric animal models also reveal that tubulointerstitial fibrosis develops, even in the absence of prominent leukocyte infiltrates after ureteral obstruction. Deleting Notch3 receptors on resident cells blunts kidney fibrosis, ablates NF-κB signaling, and lessens matrix deposition.

Conclusions Cell-specific receptor Notch3 signaling independently orchestrates leukocyte infiltration and organ fibrosis. Interference with Notch3 signaling may present a novel therapeutic approach in inflammatory as well as fibrotic diseases.

  • fibrosis
  • chronic kidney disease
  • cell signaling
  • chronic inflammation
  • cell adhesion
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (11)
Journal of the American Society of Nephrology
Vol. 31, Issue 11
November 2020
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Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression
Sabine Brandt, Tobias M. Ballhause, Anja Bernhardt, Annika Becker, Delia Salaru, Hien Minh Le-Deffge, Alexander Fehr, Yan Fu, Lars Philipsen, Sonja Djudjaj, Andreas J. Müller, Rafael Kramann, Mahmoud Ibrahim, Robert Geffers, Chris Siebel, Berend Isermann, Florian H. Heidel, Jonathan A. Lindquist, Peter R. Mertens
JASN Nov 2020, 31 (11) 2589-2608; DOI: 10.1681/ASN.2019121289

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Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression
Sabine Brandt, Tobias M. Ballhause, Anja Bernhardt, Annika Becker, Delia Salaru, Hien Minh Le-Deffge, Alexander Fehr, Yan Fu, Lars Philipsen, Sonja Djudjaj, Andreas J. Müller, Rafael Kramann, Mahmoud Ibrahim, Robert Geffers, Chris Siebel, Berend Isermann, Florian H. Heidel, Jonathan A. Lindquist, Peter R. Mertens
JASN Nov 2020, 31 (11) 2589-2608; DOI: 10.1681/ASN.2019121289
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