Abstract
Antibody-mediated glomerulonephritis (AGN) is a clinical manifestation of many autoimmune kidney diseases for which few effective treatments exist. Chronic inflammatory circuits in renal glomerular and tubular cells lead to tissue damage in AGN. These cells are targeted by the cytokine IL-17, which has recently been shown to be a central driver of the pathogenesis of AGN. However, surprisingly little is known about the regulation of pathogenic IL-17 signaling in the kidney. Here, using a well-characterized mouse model of AGN, we show that IL-17 signaling in renal tubular epithelial cells (RTECs) is necessary for AGN development. We also show that Regnase-1, an RNA binding protein with endoribonuclease activity, is a negative regulator of IL-17 signaling in RTECs. Accordingly, mice with a selective Regnase-1 deficiency in RTECs exhibited exacerbated kidney dysfunction in AGN. Mechanistically, Regnase-1 inhibits IL-17–driven expression of the transcription factor IκBξ and, consequently, its downstream gene targets, including Il6 and Lcn2. Moreover, deletion of Regnase-1 in human RTECs reduced inflammatory gene expression in a IκBξ-dependent manner. Overall, these data identify an IL-17–driven inflammatory circuit in RTECs during AGN that is constrained by Regnase-1.
Highlights
Antibody-mediated glomerulonephritis (AGN) describes a heterogenous group of renal conditions caused by an inappropriate response to renal autoantigens, such as the glomerular basement membrane (GBM) [1, 2]
renal tubular epithelial cells (RTECs)-intrinsic IL-17 signaling is critical for AGN pathology
Reconstituted recipients were evaluated for susceptibility to AGN by injecting mice with rabbit IgG in complete Freund’s adjuvant (CFA), followed 3 days later by injection with rabbit anti-GBM serum [10, 36]
Summary
Antibody-mediated glomerulonephritis (AGN) describes a heterogenous group of renal conditions caused by an inappropriate response to renal autoantigens, such as the glomerular basement membrane (GBM) [1, 2]. The majority of AGN patients progress to end-stage renal disease as a consequence of chronic tubular inflammation [7]. A landmark recent study showed that human Th17 cells specific for commensal microbes such as Staphylococcus aureus and Candida albicans contribute to AGN [20]. These findings are consistent with prior work in preclinical models that IL-17 and its adaptor Act promote AGN in mice [10,11,12,13,14, 21,22,23]. These findings demonstrate a potent, kidney-intrinsic inflammation circuit that is potentiated by RTEC-specific IL-17 signaling and restrained by Regnase-1 in a highly cell type–specific manner
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