Transendothelial migration of neutrophils affects the localization of NFκB in endothelial cells.

Severe bacterial infection or trauma frequently leads to a systemic inflammatory response, a self-reinforcing activation of neutrophils and vascular endothelial cells that can be deadly. On page 641, Cepinskas et al. describe a neutrophil-mediated signaling mechanism that inhibits inflammation. The findings demonstrate a novel function for neutrophils and a previously unknown form of immunological tolerance, and they identify a promising target for new anti-inflammatory drugs.

In systemic inflammation, circulating cytokines cause the transcription factor NFκB to translocate from the cytoplasm to the nucleus of vascular endothelial cells, where it induces the transcription of pro-inflammatory genes. Using a cell culture model of inflammation, the authors found that the migration of neutrophils across a monolayer of cytokine-activated endothelial cells causes NFκB levels in the endothelial cell nuclei to drop. Cross-linking the adhesion molecule PECAM-1 on the surface of the endothelial cells produces the same effect, suggesting that the neutrophils send anti-inflammatory signals to the endothelium through PECAM-1. Exposing the neutrophil-calmed endothelial cells to a second round of cytokine activation results in even further reduction of the pro-inflammatory response. The authors are now trying to determine what controls this novel type of induced tolerance at the molecular level. ▪