2024
Nature

The podocytes’ inflammatory responses in experimental GN are independent of canonical MYD88-dependent toll-like receptor signaling

Authors:

Thomas Schömig, Paul Diefenhardt, Ingo Plagmann, Bastian Trinsch, Tim Merz, Giuliano Crispatzu, David Unnersjö-Jess, Jasper Nies, David Pütz, Claudio Sierra Gonzalez, Bernhard Schermer, Thomas Benzing, Paul Thomas Brinkkoetter, Sebastian Brähler

Keywords:

podocyte, kidney, inflammation, MYD88, glomerulonephritis, nephrotoxic nephritis, nephritis

Abstract:

Podocytes form the kidney filtration barrier and continuously adjust to external stimuli to preserve their integrity even in the presence of inflammation. It was suggested that canonical toll-like receptor signaling, mediated by the adaptor protein MYD88, plays a crucial role in initiating inflammatory responses in glomerulonephritis (GN). We explored the influence of podocyte-intrinsic MYD88 by challenging wild-type (WT) and podocyte-specific Myd88 knockout (MyD88^pko) mice, with a model of experimental GN (nephrotoxic nephritis, NTN). Next-generation sequencing revealed a robust upregulation of inflammatory pathways and changes in cytoskeletal and cell adhesion proteins in sorted podocytes from WT mice during disease. Unchallenged MyD88^pko mice were healthy and showed no proteinuria, normal kidney function and lacked morphological changes. During NTN, MyD88^pko exhibited a transient increase in proteinuria in comparison to littermates, while histological damage, podocyte ultrastructure in STED imaging and frequencies of infiltrating immune cells by flow cytometry were unchanged. MYD88-deficiency led to subtle changes in the podocyte transcriptome, without a significant impact on the overall podocyte response to inflammation, presumably through MYD88-independent signaling pathways. In conclusion, our study reveals a comprehensive analysis of podocyte adaptation to an inflammatory environment on the transcriptome level, while MYD88-deficiency had only limited impact on the course of GN suggesting additional signaling through MYD88-independent signaling.