Characterization of a new subtype of regulated necrosis

• Applicant: Professor Dr. Stefan Krautwald
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539143574

In our preliminary work for the applied project we found that, contrary to any intuition, the simultaneous activation of the NLRP3 inflammasome and the necrosome in bone marrow-derived macrophages (BMDMs) cannot simply be considered an addition of the two independent signal transduction pathways. Since, according to our preliminary work, neither cell death modality can be blocked (individually or in combination) with a pharmacological inhibitor of either the inflammasome or necroptosis when induced simultaneously, the "dichotomous cell death" we induced in these primary cells, which is theoretically composed of an inflammatory and a necroptotic component, may thus represent a previously undescribed novel subtype of regulated cell death. Since neither NLRP3 nor MLKL, as key proteins of the inflammasome and necrosome, respectively, can be blocked in this simultaneous cell death, the question thus arises whether there is a transmitter that we do not yet know, at least in this context, and which protein ultimately executes this type of cell death. Especially from a clinical point of view, this is of immense importance, since both cell death pathways seem to be deeply interconnected in such a setting. The relative contributions of the inflammasome and necroptosis in the context of different diseases have not yet been sufficiently investigated. With the help of the proposed project, we would like to characterize the "dichotomous cell death" at the molecular level and, utilizing Nlrp3-/--ko, Mlkl-/--ko and Nlrp3-/-/Mlkl-/--dko animals, clarify whether this form of cell death also exists in vivo under pathophysiological conditions. The existence of such a new cell death modality could very well explain the inefficiency of previous therapeutic attempts directed against the NLRP3 inflammasome or necroptosis in various highly relevant human diseases. By identifying a new therapeutic target, we could thus enable a direct translation of our studies’ results into the clinic.

• DFG Programme: Research Grants