The role of cell death in inflammation and inflammation-related disorders (360G-Wellcome-214342_Z_18_Z)

We recently discovered that aberrant cell death induced by death ligands beyond TNF causes lethal inflammation induced by perturbed linear ubiquitination (linUb). Importantly, cell death induction by death ligands other than TNF requires RIPK1 kinase activity in vivo whereas TNF-induced cell death does not. Based thereupon, we will test the following interconnected hypotheses: there is a biochemical basis for the requirement of the kinase activity of RIPK1 for cell death induction by death ligands other than TNF; mice with perturbed linUb can be effectively treated by simultaneously preventing different death ligands, including TNF, but not TNF alone, from inducing cell death; the induction of aberrant cell death by a combination of death ligands, including but not only TNF, is responsible for instigating inflammation-associated diseases in humans, including diseases caused by perturbed linUb and autoimmunity; a cell death aetiology of inflammation-associated disease leaves behind a molecular signature that can be identified by combined cell death and immune profiling which, decisively, in turn reveals a cell death-driven disease aetiology in patients with inflammation-associated disease. If successful, this research should enable the future identification of patients with a cell death-driven aetiology of inflammation-associated disease and propose effective cell death-inhibitory treatment options for them.