STING1 deficiency ameliorates immune‐mediated crescentic glomerulonephritis in mice

Authors:
Publisher website
Google Scholar
Abstract
Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN. Analysis of kidney biopsies from patients with RPGN revealed increased interstitial, glomerular, and tubular expression of STING1, an accessory protein of the c‐GAS‐dependent DNA‐sensing pathway, which was also observed in murine nephrotoxic nephritis induced by an anti‐GBM antibody. STING1 was expressed by key cell types involved in RPGN and crescent formation such as glomerular parietal epithelial cells, and tubular cells as well as by inflammation accessory cells. In functional in vivo studies, Sting1−/− mice with nephrotoxic nephritis had lower kidney cytokine expression, milder kidney infiltration by innate and adaptive immune cells, and decreased disease severity. Pharmacological STING1 inhibition mirrored these findings. Direct STING1 agonism in parietal and tubular cells activated the NF‐κB‐dependent cytokine response and the interferon‐induced genes (ISGs) program. These responses were also triggered in a STING1‐dependent manner by the pro‐inflammatory cytokine TWEAK. These results identify STING1 activation as a pathological mechanism in RPGN/CGN and TWEAK as an activator of STING1. Pharmacological strategies targeting STING1, or upstream regulators may therefore be potential alternatives to treat RPGN. © 2023 The Pathological Society of Great Britain and Ireland.
Funding Information
  • Comunidad de Madrid (P2022/BMD‐7223, CIFRA_COR‐CM)
  • Fundación Conchita Rábago
  • Ministerio de Ciencia e Innovación (IJC2018‐035187‐I)
  • Sociedad Española de Nefrología
  • Instituto de Salud Carlos III (RD21/0005/0001, RICORS2040, PT20‐00141, PI22/00050, PI20/00140, PI20/00744, PI19/00815, PI19/00588, PI18/01366, PI18/01133)

This publication has 70 references indexed in Scilit: