Sorting the signals from the signals in the noisy environment of inflammation

Abstract

Necrotic cells release dozens, possibly hundreds, of molecules that stimulate the inflammatory response. Healthy cells in the environment react to these by secreting other inflammatory mediators to amplify the response. In response to acute necrotic injury in the liver, neutrophils follow a restricted set of molecular cues to move along the sinusoids through the inflamed tissue and into the zone of necrosis, as demonstrated by intravital microscopy to view leukocyte migration live and in real time. Necrosis initiates an intricate interplay between damage-associated molecular pattern molecules, stromal inflammatory cells, and neutrophils. This results in a series of clear molecular signals, enabling neutrophils to follow an intravascular chemokine gradient along the sinusoid in the region where blood still circulates and a formyl peptide gradient through the nonperfused region to the necrotic focus.