Abstract: TH-PO025

Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Melderis, Simon, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Herrnstadt, Georg Rudolf, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Nosko, Anna, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Tiegs, Gisa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Steinmetz, Oliver M., University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Background

Amphiregulin (AREG), a member of the epidermal growth factor family, plays a role in development and tumorigenesis. Recently AREG has also emerged as novel player in immune responses. Both, pro- and anti-inflammatory functions have been postulated, leaving the role of AREG in inflammatory diseases widely unclear. In particular, nothing is known about the role of AREG in glomerulonephritis (GN). Given that EGF-receptor directed therapies have recently become available, we aimed to clarify the function of AREG in an experimental model of crescentic GN.

Methods

Nephrotoxic nephritis (NTN) was induced in AREG-KO mice and wild type controls. Time course and tissue specific AREG expression was assessed. Renal histology, function and leukocyte influx were analyzed. Broad analyses of renal and systemic immune responses were performed.

Results

Renal AREG expression was undetectable under homeostatic conditions. After induction of NTN AREG mRNA levels increased within the first 5 days and peaked at day 7. Expression subsequently decreased to baseline levels at day 20. In contrast, splenic expression remained below detection level at all time points. Importantly, the course of NTN was significantly attenuated in AREG-KO mice in terms of kidney function, albuminuria and histological damage. In search of a potential mechanism, we found reduced renal expression of the pro-inflammatory cytokine IL-1β, the macrophage attracting chemokine monocyte chemotactic protein 1 (MCP-1), as well as granulocyte attracting C-X-C motif chemokine ligands 1 (CXCL1) and 5 (CXCL5). As a consequence, renal infiltration of macrophages and neutrophils was significantly impaired in AREG-KO mice. Furthermore, characterization of renal macrophage markers revealed a less inflammatory phenotype in the absence of AREG.

Conclusion

Our data strongly suggest that AREG has pro-inflammatory effects in acute GN. As one mechanism, we hypothesize, that AREG induces renal chemokine expression. This in turn results in enhanced recruitment and activation of inflammatory myeloid cells. AREG is thus a potential new therapeutic target for crescentic GN.

Funding

  • Government Support - Non-U.S.