| First Author | Fuchslocher Chico J | Year | 2018 |
| Journal | Oncotarget | Volume | 9 |
| Issue | 16 | Pages | 12941-12958 |
| PubMed ID | 29560122 | Mgi Jnum | J:278258 |
| Mgi Id | MGI:6323544 | Doi | 10.18632/oncotarget.24410 |
| Citation | Fuchslocher Chico J, et al. (2018) The enhanced susceptibility of ADAM-17 hypomorphic mice to DSS-induced colitis is not ameliorated by loss of RIPK3, revealing an unexpected function of ADAM-17 in necroptosis. Oncotarget 9(16):12941-12958 |
| abstractText | The disintegrin metalloprotease ADAM17 has a critical role in intestinal inflammation and regeneration in mice, as illustrated by the dramatically increased susceptibility of ADAM17 hypomorphic (ADAM17(ex/ex)) mice to dextran sulfate sodium (DSS)-induced colitis. Similarly, necroptosis has been implicated in inflammatory responses in the intestine. In this study, we have investigated the contribution of necroptosis to ADAM17-regulated intestinal inflammation in vivo by crossing ADAM17(ex/ex) mice with mice that lack the necroptotic core protein RIPK3. Despite the loss of RIPK3, ADAM17(ex/ex)/RIPK3(-/-) mice showed the same increased susceptibility as ADAM17(ex/ex) mice in both acute and chronic models of DSS-induced colitis. Mice of both genotypes revealed comparable results with regard to weight loss, disease activity index and colitis-associated changes of inner organs. Histopathological analyses confirmed similar tissue destruction, loss of barrier integrity, immune cell infiltration, and cell death; serum analyses revealed similar levels of the pro-inflammatory cytokine KC. Resolving these unexpected findings, ADAM17(ex/ex) mice did not show phosphorylation of RIPK3 and its necroptotic interaction partner MLKL during DSS-induced colitis, although both proteins were clearly expressed. Consistent with these findings, murine embryonic fibroblasts derived from ADAM17(ex/ex) mice were protected from tumor necrosis factor (TNF)-induced necroptosis and failed to show phosphorylation of MLKL and RIPK3 after induction of necroptosis by TNF, revealing a novel, undescribed role of the protease ADAM17 in necroptosis. |
