The essential role of lipopolysaccharide-binding protein in protection of mice against a peritoneal Salmonella infection involves the rapid inductionof an inflammatory response

Acute and chronic hyperinflammation are of major clinical concern, and many treatment strategies are therefore directed to inactivating parts of the i nflammatory system. However, survival depends on responding quickly to path ogen attack, and since the adaptive immune system requires several days to adequately react, we rely initially on a range of innate defenses, many of which operate by activating parts of the inflammatory network. For example, LPS-binding protein (LBP) can transfer the LPS of Gram-negative bacteria t o CD14 on the surface of macrophages, and this initiates an inflammatory re action. However, the importance of this chain of events in infection is unc lear. First, the innate system is redundant, and bacteria have many compone nts that may serve as targets for it. Second, LBP can transfer LPS to other acceptors that do not induce inflammation. In this study, we show that inn ate defense against a lethal peritoneal infection with Salmonella requires a direct proinflammatory involvement of LBP, and that this is a major nonre dundant function of LBP in this infection model. This emphasizes that block ing the LBP-initiated inflammatory cascade disables an essential defense pa thway. Any anti-inflammatory protection that may be achieved must be balanc ed against the risks inherent in blinding the innate system to the presence of Gram-negative pathogens.