A new study has identified a molecular ‘culprit’ responsible for causing damaging levels of cell death and inflammation in the body. The findings could lead to improved treatment options for a range of conditions driven by inflammatory cell death, including the SARS-CoV-2 virus.  

Cell death is an important part of the body’s immune response to infection. When uncontrolled, however, it can cause harmful amounts of inflammation in otherwise healthy organs and tissue. The research team uncovered how an overproduction of the molecule nitric oxide, which the protein caspase-8 helps to produce, caused dangerous levels of cell death. They showed that arresting the function of caspase-8 could prevent unregulated cell death and inflammation.

Published in Immunity, the findings highlight the potential to create drugs that block caspase-8 and nitric oxide to prevent this novel inflammatory cell death process. Manipulating this cell death pathway could lead to new and improved treatments for people living with inflammatory disease.

Nitric oxide and the protein that enables its production, caspase-8, have been shown to cause a unique form of cell death that can drive excessive levels of inflammation in the body. The team showed that blocking the activity of caspase-8 and nitric oxide in a preclinical SARS-CoV-2 model reduced the severity of inflammation and infection. The findings suggest targeting this novel cell death pathway could create new therapeutics for a range of diseases where damaging levels of nitric oxide, cell death and inflammation occur including asthma, inflammatory bowel disease and COVID-19.\

While nitric oxide is critical to the body’s circulatory and nervous systems, the recent findings link an overproduction of the molecule with excessive levels of cell death and inflammation. Cell death is critical for a healthy immune response, however, too much of it can send the immune system into overdrive and trigger inflammatory disease.

The senior author said the team was surprised to uncover that nitric oxide was a ‘killer culprit’ responsible for driving excessive cell death in the newly discovered inflammatory cell death pathway.

“Our research into the combined actions of pathogen and host inflammatory molecules in the cell death process led us directly to nitric oxide,” the senior author said.
“This led us to discover how nitric oxide is the major driving force of cell death in this particular pathway. Our study showed levels of this molecule ramped up when immune cells sensed viral and pathogenic threats. The more nitric oxide that was made, the more likely it was that cells would die.”

The team found that blocking the production of nitric oxide and the cell death protein caspase-8 reduced the severity of disease in a preclinical SARS-CoV-2 infection model.

Lead researcher said removing caspase-8 or nitric oxide in these models most likely stops cells from dying and causing tissue damage, highlighting the potential to use caspase-8 as a drug target that could block excessive cell death and the subsequent inflammatory response.

“While this is still preliminary data, we believe blocking the function of caspase-8, or the production of nitric oxide, would prevent damaging levels of inflammation,” the author said.

The team leveraged CRISPR technology systems to genetically dissect the new cell death pathway and further understand the role of the key genes involved.

“Coupled with our COVID-19 models, this technology allowed us to understand the exact role of caspase-8. Being able to understand and manipulate key genes in this pathway could lead to exciting new treatment options for diseases where damaging nitric oxide has been suggested to occur such as asthma , inflammatory bowel disease and the SARS-CoV-2 virus,” another author said.

https://www.cell.com/immunity/fulltext/S1074-7613(22)00032-2

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