Abstract
Podocytes have been proposed to be antigen presenting cells (APCs). In traditional APCs, the neonatal Fc receptor (FcRn) is required for antigen presentation and global knockout of FcRn protects against glomerulonephritis. Since podocytes express FcRn, we sought to determine whether the absence of podocyte FcRn ameliorates immune-mediated disease. We examined MHCII and costimulatory markers expression in cultured wild type (WT) and FcRn knockout (KO) podocytes. Interferon gamma (IFNγ) induced MHCII expression in both WT and KO podocytes but did not change CD80 expression. Neither WT nor KO expressed CD86 or inducible costimulatory ligand (ICOSL) at baseline or with IFNγ. Using an antigen presentation assay, WT podocytes but not KO treated with immune complexes induced a modest increase in IL-2. Induction of the anti-glomerular basement membrane (anti-GBM) model resulted in a significant decrease in glomerular crescents in podocyte-specific FcRn knockout mouse (podFcRn KO) versus controls but the overall percentage of crescents was low. To examine the effects of the podocyte-specific FcRn knockout in a model with a longer autologous phase, we used the nephrotoxic serum nephritis (NTS) model. We found that the podFcRn KO mice had significantly reduced crescent formation and glomerulosclerosis compared to control mice. This study demonstrates that lack of podocyte FcRn is protective in immune mediated kidney disease that is dependent on an autologous phase. This study also highlights the difference between the anti-GBM model and NTS model of disease.
Highlights
Despite glomerulonephritis being the third leading cause of end stage kidney disease in the United States [1], treatment options are limited and typically involve systemic immunosuppressive medications which are variably effective and have multiple side effects
In order to determine if the absence of FcRn alters podocytes ability to express major histocompatibility complex class II (MHCII) or costimulatory markers which, in turn, could affect antigen presentation, wild type (WT) and KO podocytes underwent flow cytometry for MHCII, cluster of differentiation 80 (CD80), cluster of differentiation 86 (CD86) or inducible costimulatory ligand (ICOSL) expression at baseline and after treatment of IFNγ
Podocytes have been proposed to act as antigen presenting cells (APCs) since they express some of the molecular machinery required for antigen presentation (MHCII, CD80, FcRn) and podocyte-specific KO of MHC II has been shown to attenuate anti-GBM disease [6]
Summary
Despite glomerulonephritis being the third leading cause of end stage kidney disease in the United States [1], treatment options are limited and typically involve systemic immunosuppressive medications which are variably effective and have multiple side effects. We investigated whether podocytes can function as APCs and whether knockout of FcRn in podocytes attenuates the progression of anti-glomerular basement membrane (anti-GBM) nephritis and nephrotoxic serum nephritis (NTS). We chose these models as both are well-characterized models of immune mediated kidney disease. FcRn is required for antigen presentation via MHCII, we hypothesized podocyte-specific knockout of FcRn would ameliorate antibody-mediated immune kidney disease. Podocyte-specific knockout of FcRn results in differential protection depending on the model of kidney disease immune system and takes longer to develop, we examined the effects of the podocyte-specific FcRn KO at 28 days after induction to ensure adequate time for humoral response
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