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

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Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression. / Brandt, Sabine; Ballhause, Tobias Malte; Bernhardt, Anja; Becker, Annika; Salaru, Delia; Le-Deffge, Hien Minh; Fehr, Alexander; Fu, Yan; Philipsen, Lars; Djudjaj, Sonja; Müller, Andreas J.; Kramann, Rafael ; Ibrahim, Mahmoud; Geffers, Robert; Siebel, Chris; Isermann, Berend; Heidel, Florian H.; Lindquist, Jonathan A.; Mertens, Peter R.

in: J AM SOC NEPHROL, Jahrgang 31, Nr. 11, 11.2020, S. 2589-2608.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Brandt, S, Ballhause, TM, Bernhardt, A, Becker, A, Salaru, D, Le-Deffge, HM, Fehr, A, Fu, Y, Philipsen, L, Djudjaj, S, Müller, AJ, Kramann, R, Ibrahim, M, Geffers, R, Siebel, C, Isermann, B, Heidel, FH, Lindquist, JA & Mertens, PR 2020, 'Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression', J AM SOC NEPHROL, Jg. 31, Nr. 11, S. 2589-2608. https://doi.org/10.1681/ASN.2019121289

APA

Brandt, S., Ballhause, T. M., Bernhardt, A., Becker, A., Salaru, D., Le-Deffge, H. M., Fehr, A., Fu, Y., Philipsen, L., Djudjaj, S., Müller, A. J., Kramann, R., Ibrahim, M., Geffers, R., Siebel, C., Isermann, B., Heidel, F. H., Lindquist, J. A., & Mertens, P. R. (2020). Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression. J AM SOC NEPHROL, 31(11), 2589-2608. https://doi.org/10.1681/ASN.2019121289

Vancouver

Brandt S, Ballhause TM, Bernhardt A, Becker A, Salaru D, Le-Deffge HM et al. Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression. J AM SOC NEPHROL. 2020 Nov;31(11):2589-2608. https://doi.org/10.1681/ASN.2019121289

Bibtex

@article{aa301d0f96e84e71bd1dcd6fdc29954b,
title = "Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression",
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.",
author = "Sabine Brandt and Ballhause, {Tobias Malte} and Anja Bernhardt and Annika Becker and Delia Salaru and Le-Deffge, {Hien Minh} and Alexander Fehr and Yan Fu and Lars Philipsen and Sonja Djudjaj and M{\"u}ller, {Andreas J.} and Rafael Kramann and Mahmoud Ibrahim and Robert Geffers and Chris Siebel and Berend Isermann and Heidel, {Florian H.} and Lindquist, {Jonathan A.} and Mertens, {Peter R}",
note = "Copyright {\textcopyright} 2020 by the American Society of Nephrology.",
year = "2020",
month = nov,
doi = "10.1681/ASN.2019121289",
language = "English",
volume = "31",
pages = "2589--2608",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "11",

}

RIS

TY - JOUR

T1 - Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression

AU - Brandt, Sabine

AU - Ballhause, Tobias Malte

AU - Bernhardt, Anja

AU - Becker, Annika

AU - Salaru, Delia

AU - Le-Deffge, Hien Minh

AU - Fehr, Alexander

AU - Fu, Yan

AU - Philipsen, Lars

AU - Djudjaj, Sonja

AU - Müller, Andreas J.

AU - Kramann, Rafael

AU - Ibrahim, Mahmoud

AU - Geffers, Robert

AU - Siebel, Chris

AU - Isermann, Berend

AU - Heidel, Florian H.

AU - Lindquist, Jonathan A.

AU - Mertens, Peter R

N1 - Copyright © 2020 by the American Society of Nephrology.

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

U2 - 10.1681/ASN.2019121289

DO - 10.1681/ASN.2019121289

M3 - SCORING: Journal article

VL - 31

SP - 2589

EP - 2608

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 11

ER -