The Cell Type Specific Immune Regulatory Functions of Amphiregulin in Glomerulonephritis

• Applicant: Professor Dr. Oliver Michael Steinmetz
• Subject Area: Nephrology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421050765

Glomerulonephritis (GN) remains a leading cause of end stage renal disease worldwide. Autoimmune diseases like anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis and systemic lupus erythematosus (SLE) are typical underlying pathologies. Since currently available therapies are rather non-specific and relatively toxic, the search for new and innovative therapeutic options is highly rewarding. A novel and promising therapeutic target is the multi-functional cytokine Amphiregulin (AREG). AREG belongs to the epidermal growth factor (EGF) family and mediates its effects via binding to the promiscuous EGF-receptor (EGFR). Recent studies, including our own data from the past funding period, have identified AREG as an important mediator of inflammatory diseases. A better understanding of AREG´s immune functions is highly warranted, since EGFR blockers are already in use for tumor therapy and various AREG directed compounds are currently being developed, so that they could also be applied to treat immune mediated diseases. It is of note, however, that both, pro- as well as anti-inflammatory AREG effects have been reported. In this respect, data by us and others suggest, that the cellular source of AREG might be important for the resulting function. While resident tissue cell derived AREG seems to have pro-inflammatory and pro-fibrotic effects, leukocyte derived AREG was shown to be predominantly anti-inflammatory and reparative. One main goal of the current grant application is thus to clarify the cell type specific differential roles of AREG in acute GN and chronically developing lupus nephritis to lay the groundwork for AREG directed therapies. The second main goal will be characterization of the currently ill-defined immune-regulatory mechanisms initiated by AREG signaling. Previous studies, including our data from the past funding period have pointed towards strong immunosuppressive effects of AREG on CD4+ T cell responses. We thus aim to in depth analyze the clinical relevance of this observation, and to identify the cellular players and signaling pathways involved herein. Models used will include antigen specific immunization, nephrotoxic nephritis (NTN), which resembles human rapidly progressive GN, as well as one inducible (pristane) and one genetic (MRL/lpr) model of SLE. Finally, we will translate our findings to human GN and characterize AREG expression by its different cellular sources in lupus nephritis patients from French and German collectives, using RNAseq and multiplex immunofluorescence techniques. Our findings will be correlated with clinical and histopathological data and provide the basis for evaluation of AREG as a prognostic biomarker as well as for interventions against the AREG/EGFR axis as novel option for the treatment of GN.

• DFG Programme: Research Grants