Meanwhile, other studies by the Penn group and others have shown that Toll-like receptors, or TLRs a set of proteins that also activate immune cell responses may act in concert with the complement system. In addition, mice lacking one form of TLR called TLR2 do not develop bone loss associated with periodontitis, just like the C5aR-deficient mice.
In the new study, the Penn team wanted to determine if the synergism seen by other scientists between the complement system and TLRs was also at play in this inflammatory gum disease.
To find out, they injected two types of molecules, one that activated C5aR and another that activated TLR2, into the gums of mice. When only one type of molecule was administered, a moderate inflammatory response was apparent a day later, but when both were injected together, inflammatory molecules increased dramatically soaring to levels higher than would have been expected if the effect of activating both receptors was merely additive.
This finding suggested to the scientists that the Toll-like receptor signaling was somehow involved in "crosstalk" with the complement system, serving to augment the inflammatory response. Turning that implication on its head, they wondered whether blocking just one of these receptors could effectively halt the inflammation that allows P. gingivalis and other bacteria to thrive and cause disease.
Testing this hypothesis, the researchers synthesized and administered a molecule that blocks the activity of C5aR, to see if it could prevent periodontitis from developing. They gave this receptor "antagonist," known as C5aRA, to mice that were then infected with P. gingivalis. The C5aRA injections were able to stave off inflammation to a large extent, reducing inflammatory molecules by 80 percent compared to a control, and completely stopping bone loss.
|Contact: Katherine Unger Baillie|
University of Pennsylvania