August 1, 2014

Anti-inflammatory protein “rheostat” sheds light on leaky blood vessels

Vanderbilt researchers have discovered that the protein CRADD counteracts inflammatory injury to endothelial cells, which could assist the development of new therapies for inflammatory vascular disorders.

Inflammatory signals alter the organization of endothelial cells (shown), and the protein CRADD counteracts this signaling. (Image courtesy of JBC)

Inflammation mediates many diseases and weakens the barrier function of endothelial cells lining the blood vessels. Leaky vessels cause swelling, and in severe cases, contribute to life-threatening respiratory distress, blood clots, and multiple organ failure.

Endothelial cells respond to inflammatory insults from the outside by mobilizing an intracellular signaling complex, the CARMA3 signalosome, which is linked to NFkappaB, the master regulator of inflammation.

In a paper published online in June by the Journal of Biological Chemistry, Huan Qiao, M.D., and colleagues in the laboratory of Jacek Hawiger, M.D., Ph.D., report that a protein called CRADD, which is produced in human and mouse endothelial cells, counteracts inflammatory signals by interacting with the protein BCL10, a component of the CARMA3 signalosome.

CRADD-deficient human and mouse endothelial cells displayed more inflammation and leakiness of endothelial monolayers when challenged with bacterial endotoxin or the clotting enzyme, thrombin. Barrier function was restored when these cells were replenished with a novel recombinant cell-penetrating CRADD protein bioengineered by Hawiger’s group.

Thus, CRADD has a newly identified role as a kind of physiological “rheostat” that counteracts inflammatory injury to endothelial cells. This discovery may assist development of new therapies for inflammatory vascular disorders that disrupt endothelial integrity.

This work was supported by National Institutes of Health Grants HL069452, HL085833, and AA015752 and HL069765, the Vanderbilt Immunotherapy Program and the Department of Medicine.

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