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Enzyme's newly discovered role may make it target for arthritis treatment

look for the mechanisms by which these proteases regulate inflammation.

Observations made by Pham's lab and other groups had linked the earliest stages of inflammation in the animal models to neutrophils, which are a kind of immune system firestarter. They arrive first at sites of injury, infection or irritation and secrete chemicals that bring in secondary waves of other immune attack cells.

"The contributions of the neutrophil weren't always appreciated by scientists," Pham notes. "When patients come to their doctors with arthritis symptoms, the inflammation typically is so well-established that neutrophils are no longer the predominant cell type."

Animal models of inflammation let scientists watch all stages of the inflammatory process and allowed them to see how important neutrophils are to the early stages of that process.

In the new study, Pham and her colleagues showed that cathepsin G is secreted by neutrophils, binds to the cells' surface membranes, and affects the rearrangement of integrins, an important group of adhesion compounds on the surface of neutrophils.

"The way these integrins rearrange and cluster on the cell surface can send a signal back into the cell that modifies the cell's behavior, allowing it to do things like secrete inflammatory factors," Pham explains. "The proteases' ability to affect integrin rearrangement is dependent on their catalytic activity, and that's an ability that can be taken away from them."

Pham suspects this class of proteases may also be making significant contributions to other autoimmune and inflammatory conditions besides arthritis. She plans further studies to investigate this possibility. Her lab is also working to determine what molecules cathepsin G is sticking to and interacting with on the surfaces of neutrophils and other cells.

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Raptis SZ, Shapiro SD, Simmons PM, Cheng AM, Pham CTN. Serine protease Cathepsin G regulates adhesion-dependent ne
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Source:Washington University School of Medicine


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