Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis

Christian Hemmers; Corinna Schulte; Julia Wollenhaupt; Dickson W L Wong; Eva Harlacher; Setareh Orth-Alampour; Barbara Mara Klinkhammer; Stephan H Schirmer; Michael Böhm; Nikolaus Marx; Thimoteus Speer; Peter Boor; Joachim Jankowski; Heidi Noels

doi:10.3390/biomedicines10020420

Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis

Christian Hemmers, Corinna Schulte, Julia Wollenhaupt, Dickson W L Wong, Eva Harlacher, Setareh Orth-Alampour, Barbara Mara Klinkhammer, Stephan H Schirmer, Michael Böhm, Nikolaus Marx, Thimoteus Speer, Peter Boor, Joachim Jankowski, Heidi Noels^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3-4 fold; CCL9: 3-5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis.

Original language	English
Article number	420
Number of pages	12
Journal	Biomedicines
Volume	10
Issue number	2
DOIs	https://doi.org/10.3390/biomedicines10020420
Publication status	Published - 10 Feb 2022

Keywords

ACTIVATION
CARDIOVASCULAR-DISEASE
CCL6
CCL9
EXPRESSION
INSIGHTS
MACROPHAGES
MECHANISMS
MIP-1 gamma
MONOCYTE CHEMOATTRACTANT PROTEIN-1
MOUSE
RECEPTOR CCR1
RENAL FIBROSIS
chemokine
chronic kidney disease
collagen
fibrosis
inflammation
macrophage

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Hemmers, C., Schulte, C., Wollenhaupt, J., Wong, D. W. L., Harlacher, E., Orth-Alampour, S., Klinkhammer, B. M., Schirmer, S. H., Böhm, M., Marx, N., Speer, T., Boor, P., Jankowski, J., & Noels, H. (2022). Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis. Biomedicines, 10(2), Article 420. https://doi.org/10.3390/biomedicines10020420

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title = "Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis",

abstract = "Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3-4 fold; CCL9: 3-5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis.",

keywords = "ACTIVATION, CARDIOVASCULAR-DISEASE, CCL6, CCL9, EXPRESSION, INSIGHTS, MACROPHAGES, MECHANISMS, MIP-1 gamma, MONOCYTE CHEMOATTRACTANT PROTEIN-1, MOUSE, RECEPTOR CCR1, RENAL FIBROSIS, chemokine, chronic kidney disease, collagen, fibrosis, inflammation, macrophage",

author = "Christian Hemmers and Corinna Schulte and Julia Wollenhaupt and Wong, {Dickson W L} and Eva Harlacher and Setareh Orth-Alampour and Klinkhammer, {Barbara Mara} and Schirmer, {Stephan H} and Michael B{\"o}hm and Nikolaus Marx and Thimoteus Speer and Peter Boor and Joachim Jankowski and Heidi Noels",

note = "Funding Information: Funding: This work was supported by the German Research Foundation (DFG) Project-ID 322900939— SFB/TRR219 (to M.B., N.M., T.S., P.B., J.J., H.N.), Project-ID 403224013—SFB1382 (to H.N. and J.J.), Project-ID 454024652 (to P.B.) and Project-ID 445703531 (to P.B., B.M.K.). Funding was also provided by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement No 101001791 (to P.B.)) and the “Else Kr{\"o}ner-Fresenius-Stiftung” (Project 2020_EKEA.60 to H.N). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = feb,

day = "10",

doi = "10.3390/biomedicines10020420",

language = "English",

volume = "10",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "2",

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Hemmers, C, Schulte, C, Wollenhaupt, J, Wong, DWL, Harlacher, E, Orth-Alampour, S, Klinkhammer, BM, Schirmer, SH, Böhm, M, Marx, N, Speer, T, Boor, P, Jankowski, J & Noels, H 2022, 'Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis', Biomedicines, vol. 10, no. 2, 420. https://doi.org/10.3390/biomedicines10020420

TY - JOUR

T1 - Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis

AU - Hemmers, Christian

AU - Schulte, Corinna

AU - Wollenhaupt, Julia

AU - Wong, Dickson W L

AU - Harlacher, Eva

AU - Orth-Alampour, Setareh

AU - Klinkhammer, Barbara Mara

AU - Schirmer, Stephan H

AU - Böhm, Michael

AU - Marx, Nikolaus

AU - Speer, Thimoteus

AU - Boor, Peter

AU - Jankowski, Joachim

AU - Noels, Heidi

N1 - Funding Information: Funding: This work was supported by the German Research Foundation (DFG) Project-ID 322900939— SFB/TRR219 (to M.B., N.M., T.S., P.B., J.J., H.N.), Project-ID 403224013—SFB1382 (to H.N. and J.J.), Project-ID 454024652 (to P.B.) and Project-ID 445703531 (to P.B., B.M.K.). Funding was also provided by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 101001791 (to P.B.)) and the “Else Kröner-Fresenius-Stiftung” (Project 2020_EKEA.60 to H.N). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/2/10

Y1 - 2022/2/10

N2 - Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3-4 fold; CCL9: 3-5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis.

AB - Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3-4 fold; CCL9: 3-5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis.

KW - ACTIVATION

KW - CARDIOVASCULAR-DISEASE

KW - CCL6

KW - CCL9

KW - EXPRESSION

KW - INSIGHTS

KW - MACROPHAGES

KW - MECHANISMS

KW - MIP-1 gamma

KW - MONOCYTE CHEMOATTRACTANT PROTEIN-1

KW - MOUSE

KW - RECEPTOR CCR1

KW - RENAL FIBROSIS

KW - chemokine

KW - chronic kidney disease

KW - collagen

KW - fibrosis

KW - inflammation

KW - macrophage

U2 - 10.3390/biomedicines10020420

DO - 10.3390/biomedicines10020420

M3 - Article

C2 - 35203629

SN - 2227-9059

VL - 10

JO - Biomedicines

JF - Biomedicines

IS - 2

M1 - 420

ER -