TY - JOUR T1 - Antibody-induced glomerulonephritis is amplified by RTEC-intrinsic IL-17 signaling and restrained by IL-17-mediated induction of the endoribonuclease Regnase-1 (<em>Zc3h12a</em>) JF - bioRxiv DO - 10.1101/2021.01.11.425972 SP - 2021.01.11.425972 AU - De-Dong Li AU - Rami Bechara AU - Kritika Ramani AU - Chetan V. Jawale AU - Yang Li AU - Jay K. Kolls AU - Sarah L. Gaffen AU - Partha S. Biswas Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/10/2021.01.11.425972.abstract N2 - 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 an IκBξ-dependent manner. Overall, these data identify an IL-17-driven inflammatory circuit in RTECs during AGN that is constrained by Regnase-1.Competing Interest StatementThe authors have declared no competing interest. ER -