Looking within cells to control inflammation

blood_vessel_shutterstock_142125664Chronic, unresolved inflammation can be quite harmful, right down to the cellular level. At the macro level, it has links to cancer, diabetes, heart disease and other degenerative conditions.

This is why the body keeps a tight rein on the inflammatory response and maintains a host of factors that resolve inflammation once the need for it (for instance, to clear an infection or heal an injury) has passed.

We know pretty well which factors work between cells to turn on and turn off inflammation. That knowledge has led to the development of drugs like ibuprofen, acetaminophen and naproxen, all of which temper pro-inflammatory factors.

However, when you look at the signals and signaling pathways within cells, things get more complex, especially when it comes to factors that turn off inflammation. We haven’t completely grasped the full complement of proteins that transmit these internal anti-inflammatory signals. If we did, we could potentially add new drugs to our pharmacopeia to regulate or resolve inflammation or maintain cells in a non-inflamed state, and perhaps help prevent rejection of transplanted organs and tissues.

David Briscoe, MD, and his team at Boston Children’s Hospital’s Transplant Research Program, has taken the field one step closer to grasping those internal pathways by studying a cellular protein called DEPTOR.

DEPTOR (which stands for “DEP domain-containing mTOR-interacting protein”) shuts off one of the key routes in the cell’s signaling network, a pathway called mTOR. This pathway has a hand in just about everything a cell does: growth, survival, movement, intracellular communication—you name it.

Briscoe and his team have studied DEPTOR in the vascular endothelial cells that line our blood vessels. These cells influence inflammation by producing factors that help immune cells cross out of the blood stream to the site of injury or infection. In a recent paper in the journal Blood, Briscoe and his team found that reducing levels of DEPTOR allows endothelial cells to freely produce inflammatory signals and interact with immune cells.

The team also took the understanding of DEPTOR’s effects a step further. Turning DEPTOR off in cultured endothelial cells revved up mTOR activity—along with activity of another potent signaling pathway, the MAPK pathway, and related signaling networks.

“DEPTOR is recognized in the cancer field, but ours is the first study to suggest that it could have a crucial role to play as an endogenous regulator of inflammation and angiogenesis.”

What’s more, shutting DEPTOR down promoted angiogenesis—the growth of blood vessels—by allowing endothelial cells to migrate more quickly.

Briscoe’s results to date make a convincing case that DEPTOR may fill a key niche in the inflammatory response, and suggest that it’s a powerful intracellular anti-inflammatory factor. But while suppressing DEPTOR promoted inflammation and the blood vessel growth that supports wound healing, Briscoe has yet to show what would happen if an endothelial cell was to sustain or produce unusually high levels of DEPTOR. Would it help patients with inflammatory conditions, or prevent the body from rejecting a transplant?

With the help of Boston Children’s Technology and Innovation Development Office, Briscoe has entered into an agreement with Pfizer aimed at further understanding DEPTOR’s inflammatory roles in vivo and investigating whether the protein’s activity factors into transplant rejection.

“DEPTOR is recognized in the cancer field, but ours is the first study to suggest that it could have a crucial role to play as an endogenous regulator of inflammation and angiogenesis,” Briscoe says. “The protein and other factors in the cell that regulate it could therefore be attractive targets for anti-inflammatory or anti-angiogenic research.”