Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells

Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells

Recent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown. The nephrotoxic nephritis model of GN was studied in AREG mi...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology Vol. 31; no. 9; pp. 1996 - 2012
Main Authors: Melderis, Simon, Hagenstein, Julia, Warkotsch, Matthias Tobias, Dang, Julien, Herrnstadt, Georg Rudolf, Niehus, Christoph Benjamin, Neumann, Katrin, Panzer, Ulf, Berasain, Carmen, Avila, Matias A, Tharaux, Pierre-Louis, Tiegs, Gisa, Steinmetz, Oliver M
Format: Journal Article
Language:English
Published: United States American Society of Nephrology 01-09-2020
Subjects:
Amphiregulin - physiology
Animals
Basic Research
Cell Movement
Cells, Cultured
Chemokines - biosynthesis
ErbB Receptors - physiology
Glomerulonephritis - etiology
Glomerulonephritis - pathology
Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis
Humans
Macrophages - physiology
Mice
Mice, Inbred C57BL
Myeloid Cells - physiology
macrophages
cytokines
glomerular disease
immunology
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Summary:Recent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown. The nephrotoxic nephritis model of GN was studied in AREG mice after bone marrow transplantation, and in mice with myeloid cell-specific EGFR deficiency. Therapeutic utility of AREG neutralization was assessed. Furthermore, AREG's effects on renal cells and monocytes/macrophages (M/M) were analyzed. Finally, we evaluated AREG expression in human renal biopsies. Renal AREG mRNA was strongly upregulated in murine GN. Renal resident cells were the most functionally relevant source of AREG. Importantly, the observation that knockout mice showed significant amelioration of disease indicates that AREG is pathogenic in GN. AREG enhanced myeloid cell responses inducing chemokine and colony stimulating factor 2 (CSF2) expression in kidney resident cells. Furthermore, AREG directly skewed M/M to a proinflammatory M1 phenotype and protected them from apoptosis. Consequently, anti-AREG antibody treatment dose-dependently ameliorated GN. Notably, selective abrogation of EGFR signaling in myeloid cells was sufficient to protect against nephritis. Finally, strong upregulation of AREG expression was also detected in kidneys of patients with two forms of crescentic GN. AREG is a proinflammatory mediator of GN ( ) enhancing renal pathogenic myeloid cell infiltration and ( ) direct effects on M/M polarization, proliferation, and cytokine secretion. The AREG/EGFR axis is a potential therapeutic target for acute GN.
Bibliography:S.M. and J.H. contributed equally to this work.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2019111215