Exploiting the neonatal crystallizable fragment receptor to treat kidney disease

Abstract

The neonatal Fc receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been utilized in many disease treatments including a new class of agents that were developed to inhibit FcRn for treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to utilize FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefit, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss what renal diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases.

Keywords: Albumin; Immunoglobulin G (IgG); Podocytes; neonatal Fc receptor (FcRn).

Figure 1.. FcRn expression in the Kidney.

The Table indicates human cell types known to express FcRn during health, AKI, and CKD. +, FcRn present at either protein or RNA level; NS, non-significant by scRNA-seq. * Denotes expression seen using sc-RNA-seq. The “?” refers to lack of data in healthy human tissue but has RNA data in rats. Podocytes, green; Endothelial cells, red; Proximal tubule epithelial cells (PCT), light blue; Parietal Epithelial cells, purple; Mesangial cells, pale orange; Peritubular dendritic cells, dark blue; Peritubular macrophages, yellow; Monocytes, orange.

Figure 2.. FcRn-mediated trafficking of albumin or monomeric IgG.

Albumin is endocytosed by megalin/cubilin and IgG is taken up by a yet to be discovered Fc receptor. After endocytosis, albumin or monomeric IgG is believed to be trafficked to the early endosome (EE). Binding of FcRn to albumin or monomeric IgG occurs in the acidic pH of the late endosome (LE). Albumin or monomeric IgG bound to FcRn is trafficked to the recycling endosome (RE) and ultimately these vesicles fuse with the plasma membrane to release albumin or IgG back into the circulation (recycling) or across the cell from apical to basal cell membrane (transcytosis). FcRn may be recycled back from the recycling endosome to the late endosome although this has not been directly proven.

Figure 3.. FcRn-mediated trafficking of immune complexes.

A, Immune complexes (ICs) are taken up by a yet to be discovered Fc receptor. After endocytosis, ICs are thought to be trafficked to the early endosome (EE). ICs bind FcRn in the acidic pH of the late endosome (LE) and are then directed to the lysosome for proteolytic degradation of the IC. The IgG and FcRn are then presumed to be trafficked to the recycling endosome (RE) and subsequently the cell surface where the IgG re-enters circulation. FcRn is then presumed to be recycled back to the early endosome. B, Live cell images of a podocyte with vesicles containing GFP-labeled immune complexes (green) and lysosomes stained with Lysotracker Red. Merged images show significant colocalization of ICs and lysosomes (yellow vesicles). Mouse podocytes were treated with GFP-labeled ICs for 4 hours prior to staining with Lysotracker Red and imaging on a confocal microscope. Scale bar, 10 μm.