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
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Johaiber Fuchslocher Chico1,*, Maren Falk-Paulsen2,*, Anne Luzius2, Carina Saggau1, Barbara Ruder3, Julia Bolik4, Dirk Schmidt-Arras4, Andreas Linkermann5, Christoph Becker3, Philip Rosenstiel2, Stefan Rose-John4 and Dieter Adam1
1Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, 24105 Kiel, Germany
2Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität zu Kiel, 24105 Kiel, Germany
3Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
4Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, 24118 Kiel, Germany
5Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus, 01307 Dresden, Germany
*These authors have contributed equally to this work
Dieter Adam, email: firstname.lastname@example.org
Keywords: ADAM17; DSS; colitis; RIPK3; necroptosis
Received: November 11, 2017 Accepted: January 25, 2018 Published: February 05, 2018
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 (ADAM17ex/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 ADAM17ex/ex mice with mice that lack the necroptotic core protein RIPK3. Despite the loss of RIPK3, ADAM17ex/ex/RIPK3-/- mice showed the same increased susceptibility as ADAM17ex/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, ADAM17ex/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 ADAM17ex/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.
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