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The diverse role of RIP kinases in necroptosis and inflammation
John Silke1, James A Rickard1, Motti Gerlic2
11] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Australia.
Abstract:
Inflammation is a healthy response to infection or danger and should be rapid, specific and terminated once the threat has passed. Inflammatory diseases, where this regulation fails, cause considerable human suffering. Treatments have successfully targeted pro-inflammatory cytokines, such as tumor-necrosis factor (TNF), that directly induce genes encoding inflammatory products. Inflammatory signals, including TNF, may also directly induce caspase-independent cell death (necroptosis), which can also elicit inflammation. Necroptosis was originally defined as being dependent on the kinase RIPK1 but is now known to be dependent on RIPK3 and the pseudo-kinase MLKL. Therefore, RIPK1, RIPK3 and MLKL are potential therapeutic targets. RIPK1 and RIPK3 also directly regulate inflammatory signaling, which complicates interpretation of their function but might alter their therapeutic utility. This Review examines the role of cell death, particularly necroptosis, in inflammation, in the context of recent insights into the roles of the key necroptosis effector molecules RIPK1, RIPK3 and MLKL.
Insights
Inflammatory diseases arise from dysregulated inflammation. This review explores necroptosis, a cell death pathway involving RIPK1, RIPK3, and MLKL, as a potential therapeutic target for inflammatory conditions.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Inflammation is a crucial immune response that can become detrimental when dysregulated, leading to inflammatory diseases.
- Targeting pro-inflammatory cytokines like tumor necrosis factor (TNF) has shown therapeutic success.
- TNF signaling can also trigger necroptosis, a form of programmed cell death that can exacerbate inflammation.
Purpose of the Study:
- To review the role of necroptosis in inflammation.
- To discuss the key molecules involved in necroptosis: RIPK1, RIPK3, and MLKL.
- To explore the therapeutic potential of targeting necroptosis pathways.
Main Methods:
- Literature review of recent research on necroptosis and inflammation.
- Analysis of the roles of RIPK1, RIPK3, and MLKL in cell death and inflammatory signaling.
- Examination of the interplay between necroptosis effectors and inflammatory pathways.
Main Results:
- Necroptosis, dependent on RIPK3 and MLKL, is a significant contributor to inflammation.
- RIPK1, RIPK3, and MLKL are key regulators and potential therapeutic targets in necroptosis.
- The dual role of RIPK1 and RIPK3 in both cell death and inflammatory signaling presents complex therapeutic considerations.
Conclusions:
- Necroptosis is a critical inflammatory process mediated by RIPK1, RIPK3, and MLKL.
- Targeting these molecules offers potential therapeutic strategies for inflammatory diseases.
- Understanding the complex functions of RIPK1 and RIPK3 is crucial for developing effective treatments.
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