EGF-Receptor-Dependent TLR7 Signaling in Macrophages Promotes Glomerular Injury in Crescentic Glomerulonephritis.

Narihito Tatsumoto, Suguru Saito, Ian R Rifkin, Ramon G Bonegio, Daniel N Leal, Ganes C Sen, Moshe Arditi, Michifumi Yamashita

Laboratory investigation; a journal of technical methods and pathology 2023 Sep

filter terms:

Glomerulonephritis (GN) is a group of inflammatory diseases and an important cause of morbidity and mortality worldwide. The initiation of the inflammatory process is quite different for each type of GN; however, each GN is characterized commonly and variably by acute inflammation with neutrophils and macrophages and crescent formation, leading to glomerular death. Toll-like receptor (TLR) 7 is a sensor for self-RNA and implicated in the pathogenesis of human and murine GN. Here, we show that TLR7 exacerbates glomerular injury in nephrotoxic serum nephritis (NTN), a murine model of severe crescentic GN. TLR7-/- mice were resistant to NTN, although TLR7-/- mice manifested comparable immune-complex deposition to wild-type mice without significant defects in humoral immunity, suggesting that endogenous TLR7 ligands accelerate glomerular injury. TLR7 was expressed exclusively in macrophages in glomeruli in GN but not in glomerular resident cells or neutrophils. Furthermore, we discovered that epidermal growth factor receptor (EGFR), a receptor-type tyrosine kinase, is essential for TLR7 signaling in macrophages. Mechanistically, EGFR physically interacted with TLR7 upon TLR7 stimulation, and EGFR inhibitor completely blocked the phosphorylation of TLR7 tyrosine residue(s). EGFR inhibitor attenuated glomerular damage in wild-type mice, and no additional glomerular protective effects by EGFR inhibitor were observed in TLR7-/- mice. Finally, mice lacking EGFR in macrophages were resistant to NTN. This study clearly demonstrated that EGFR-dependent TLR7 signaling in macrophages is essential for glomerular injury in crescentic GN. Copyright © 2023 United States & Canadian Academy of Pathology. All rights reserved.

Citation

Narihito Tatsumoto, Suguru Saito, Ian R Rifkin, Ramon G Bonegio, Daniel N Leal, Ganes C Sen, Moshe Arditi, Michifumi Yamashita. EGF-Receptor-Dependent TLR7 Signaling in Macrophages Promotes Glomerular Injury in Crescentic Glomerulonephritis. Laboratory investigation; a journal of technical methods and pathology. 2023 Sep;103(9):100190