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Decades-old mystery about the death of cells uncovered by scientists.

Walter and Eliza Hall Institute researchers have for the first time revealed how dying cells are hidden from the immune ‘police’ that patrol the body.  The research answers a decades-old mystery about the death of cells, which in some situations can alert the immune system to potential danger, but in other circumstances occurs ‘silently’, unnoticed by immune cells.  The study is published in the journal Cell.

Silent cell death, or apoptosis, is a controlled way for the body to eliminate cells that may be damaged, old, or surplus to the body’s requirements, without causing collateral damage. This ‘normal’ cell death process is ignored by the immune system. In contrast, the death of cells at sites of infection or damage can alert the immune system to be on the lookout for danger.

The team focused on the role of proteins called caspases.  Caspases hasten cell death by breaking down key components within the dying cell.  Because apoptosis can still occur without the involvement of caspases, the team investigated whether these proteins play any other role during cell death.

The current study found that when cells undergo apoptosis without caspases, they release immune cell signaling molecules called interferons that set off the immune response.  By dissecting the step-by-step process that occurs within dying cells, the researchers showed one of the key roles of caspases is to suppress interferon release. This confirmed that caspases are crucial for hiding apoptotic cell death from the immune system.

The team state that the discovery provided new insights into the links between cell death, the immune system and disease. A person’s health relies on their immune system’s ability to distinguish between the millions of cells that are supposed to die in the body every day to make space for new cells, and the unexpected death of cells that signals danger.  The over-reaction of immune cells to apoptosis may be a factor contributing to inflammatory diseases such as rheumatoid arthritis.

The researchers summise that the findings also provide important insights into how the body may tolerate potential new drugs.  Caspase-inhibiting medications are currently in clinical trials, for example being tested for their potential to keep cells alive during organ transplants. However, the work suggests that any use of these medications should be accompanied by careful monitoring of their effects on the immune system.

Source:  The Walter and Eliza Hall Insitute of Medical Research

 

Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.  Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production.   Kile et al 2014.
Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent. Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production. Kile et al 2014.

 

 

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