Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

Abstract

The cell death receptor Fas plays a role in the establishment of fulminant hepatitis, a major cause of druginduced liver failure. Fas activation elicits extrinsic apoptotic and hepatoprotective signals; however, the mechanisms by which these signals are integrated during disease are unknown. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls the critical sheddase a disintegrin and metalloproteinase 17 (ADAM17) and may dictate stress signaling. Using mice and cells lacking TIMP3, ADAM17, and ADAM17-regulated cell surface molecules, we have found that ADAM17-mediated ectodomain shedding of TNF receptors and EGF family ligands controls activation of multiple signaling cascades in Fas-induced hepatitis. We demonstrated that TNF signaling promoted hepatotoxicity, while excessive TNF receptor 1 (TNFR1) shedding in Timp3 -/-mice was protective. Compound Timp3 -/-Tnf -/-and Timp3 -/-Tnfr1 -/-knockout conferred complete resistance to Fas-induced toxicity. Loss of Timp3 enhanced metalloproteinase-dependent EGFR signaling due to increased release of the EGFR ligands TGF-α, amphiregulin, and HB-EGF, while depletion of shed amphiregulin resensitized Timp3 -/-hepatocytes to apoptosis. Finally, adenoviral delivery of Adam17 prevented acetaminophen-induced liver failure in a clinically relevant model of Fas-dependent fulminant hepatitis. These findings demonstrate that TIMP3 and ADAM17 cooperatively dictate cytokine signaling during death receptor activation and indicate that regulated metalloproteinase activity integrates survival and death signals during acute hepatotoxic stress.

Mitochondrial Ca2+ and ROS take center stage to orchestrate TNF-α–mediated inflammatory responses

“…For example, a mutation in the gene encoding TNFR1 that impairs receptor shedding causes TNF receptor-associated periodic syndrome (TRAPS), an autosomal-dominant autoinf lammatory disease (18). Consistent with the findings of Rowlands et al (5), a protective role of TNFR1 shedding by TACE was also reported in TNF-α sensitization of hepatocytes to Fas-mediated death (19).…”

Tissue Inhibitor of Metalloproteinases–3 Moderates the Proinflammatory Status of Macrophages

“…target in Fas-induced apoptosis in the liver (47). Our findings, however, that TIMP-3 moderates the macrophage response to apoptotic stimuli suggest that TIMP-3 is a crucial factor in determining whether proinflammatory, recruited macrophages are cleared appropriately after lung injury.…”

“…TIMP-3 has long been associated with apoptosis, and is generally thought to be proapoptotic. The overexpression of TIMP-3 in a number of different cell lines leads to the stabilization of cell-surface "death receptors" (Fas and TNFR), increased caspase activation, and cell death (42)(43)(44)(45)(46)(47). Although our finding that Timp3 2/2 BMDMs were resistant to sFasL-induced apoptosis supports these previous studies, we have been unable to demonstrate increased Fas shedding from Timp3 -/-cells, as might be predicted (data not shown).…”

Prolidase Directly Binds and Activates Epidermal Growth Factor Receptor and Stimulates Downstream Signaling

“…All of these ligands contain one or more of the conserved EGF motif (CX 7 CX 4 -5 CX 10 -13 CXCX 8 GXRC, where X represents any amino acid) (7,8), but they differ in receptor specificity (9). Moreover, all ligands are synthesized as transmembrane precursors and are released by ectodomain shedding via proteolysis (10).…”