iRhom2-dependent ADAM17 activity in inflammation models

Based on this knowledge, we produced knock-in mice (iRhom2W538S/W538S) with a point mutation in iCERES of iRhom2 in cooperation with Dr Radislav Selacek and Dr Petr Kasparek (Laboratory of Transgenic Models of Diseases; Prague) [1]. With these mice, our in vitro results regarding iCERES (Project B) could be confirmed ex vivo and in vivo. Among other things, we observed a loss of ADAM17-dependent release of pro-inflammatory mediators such as TNFα and IL-6 receptor. Since iRhom2, in contrast to iRhom1, plays a more essential role in the immune system and in inflammatory processes, these knock-in mice are suitable to study iRhom2-dependent ADAM17 activity in different inflammatory models. Our mice have a significant advantage over already established iRhom knock-out mice: It was recently shown that the different knock-out strategies used for iRhom1 and iRhom2 lead to different phenotypes and thus to contradictory results in different models, as either gene fragments continue to be expressed or a complete knock-out of the gene disrupts the regulation of neighbouring genes. Our mice, on the other hand, have a clearly defined point mutation in which iRhom2 continues to be expressed but then gets stuck in the ER with ADAM17.

References

[1] Düsterhöft, S., et al. (2021). "The iRhom homology domain is indispensable for ADAM17-mediated TNFalpha and EGF receptor ligand release." Cell Mol Life Sci 78(11):5015-5040. DOI: 10.1007/s00018-021-03845-3