TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation

Abstract

TWEAK, a member of the TNF superfamily, binds to the Fn14 receptor, eliciting biological responses. EGFR signalling is involved in experimental renal injury. Our aim was to investigate the relationship between TWEAK and EGFR in the kidney. Systemic TWEAK administration into C57BL/6 mice increased renal EGFR phosphorylation, mainly in tubular epithelial cells. In vitro, in these cells TWEAK phosphorylated EGFR via Fn14 binding, ADAM17 activation and subsequent release of the EGFR ligands HB-EGF and TGFα. In vivo the EGFR kinase inhibitor Erlotinib inhibited TWEAK-induced renal EGFR activation and downstream signalling, including ERK activation, up-regulation of proinflammatory factors and inflammatory cell infiltration. Moreover, the ADAM17 inhibitor WTACE-2 also prevented those TWEAK-induced renal effects. In vitro TWEAK induction of proinflammatory factors was prevented by EGFR, ERK or ADAM17 inhibition. In contrast, EGFR transactivation did not modify TWEAK-mediated NF-κB activation. Our data suggest that TWEAK transactivates EGFR in the kidney, leading to modulation of downstream effects, including ERK activation and inflammation, and suggest that inhibition of EGFR signalling could be a novel therapeutic tool for renal inflammation.

Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury

“…[52][53][54] In cultured tubular cells, TWEAK transactivates the EGFR pathway through recruitment of ADAM17 (a disintegrin and metalloproteinase) and subsequent shedding of the EGFR ligands transforming growth factor (TGF)-α and HB-EGF. 55 TWEAK/ADAM17/ EGFR pathway activation regulates acute renal inflammation through ERK activation and proinflammatory cytokine production, but EGFR transactivation did not modify TWEAK-mediated NF-κB activation. 55 These data suggest that EGFR blockade could be another therapeutic tool to modulate TWEAK-induced renal inflammation.…”

“…55 TWEAK/ADAM17/ EGFR pathway activation regulates acute renal inflammation through ERK activation and proinflammatory cytokine production, but EGFR transactivation did not modify TWEAK-mediated NF-κB activation. 55 These data suggest that EGFR blockade could be another therapeutic tool to modulate TWEAK-induced renal inflammation. Figure 2.…”

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

“…Importantly, this transactivation is iRhom2/ADAM17 dependent. Moreover, transactivation of the EGFR by other factors, such as CXCL1 and TNF-like weak inducer of apoptosis (TWEAK) (60,61), and most likely also via iRhom2/ADAM17, could also contribute to EGFR activation in Fcgr2b -/-kidneys. In addition, other iRhom2/ADAM17 substrates, such as IL-6R, may also contribute to renal damage in this model (62)(63)(64), which requires future study.…”

Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

“…DECEMBER 23, 2016 • VOLUME 291 • NUMBER 52 include EGFR ligands, TGF␣ and HB-EGF (heparin-binding EGF-like growth factor), and/or transactivation pathways (ADAM17, ANGII (angiotensin II), TWEAK/Fn14) (4,40).…”