Completed Infection & Immunity Cells, Biochemistry & Physiology

The role of cell death in inflammation and inflammation-related disorders

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £2.5M
Period Jan 2019 — Dec 2024

In plain English

AI plain-English summary

A faulty cell-death alarm system can trigger lethal inflammation, and scientists have now identified the specific molecular switch responsible. The problem is that inflammation—the body’s response to injury or infection—can become dangerously self-sustaining. When cells die in the wrong way, they release signals that whip up more inflammation, which in turn kills more cells. This vicious cycle is suspected in autoimmune diseases and certain inflammatory conditions, but doctors have lacked a way to tell whether a patient’s disease is driven by this cell-death mechanism or by something else. This project tests the idea that a protein called RIPK1 acts as a master switch for the dangerous type of cell death triggered by multiple death signals—not just the well-known TNF molecule. If the researchers are right, blocking RIPK1 or a combination of death signals could break the cycle. They also aim to find a molecular “signature” left behind when cell death drives disease. If successful, this fundamental science could eventually allow clinicians to identify patients whose inflammation is driven by aberrant cell death and treat them with drugs that stop that death, rather than using broad immunosuppressants. That would be a shift from treating symptoms to targeting the root cause.

View original technical description
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.

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Researchers

Henning Walczak (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Harnessing TNF-mediated cell death in cancer
TNF-receptor trafficking and the regulation of inflammation, cell death and cancer
Investigation of novel apoptotic and autophagic regulators of tumour cell death
B13 - Harnessing Cell Death Mechanisms in Cancer
Defining the roles and functional interdependencies of linear ubiquitin-related deubiquitinases and LUBAC in TNFR1 signalling

Original classification

Investigator Award in Science

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