Neutrophils in acute inflammation - current concepts and translational implications.

Modulation of neutrophil recruitment and function is crucial for targeting inflammatory cells to sites of infection to combat invading pathogens while at the same time limiting host tissue injury or autoimmunity. The underlying mechanisms regulating recruitment of neutrophils, one of the most abundant inflammatory cells, have gained increasing interest over the years. The previously described classical recruitment cascade of leukocytes has been extended to include not only capturing, rolling, adhesion, crawling and transmigration but furthermore a reverse-transmigration step that is crucial for balancing immune defense and control of remote organ endothelial leakage. Current developments in the field emphasize the importance of cellular interplay, tissue-environmental cues, circadian rhythmicity, detection of neutrophil phenotypes, differential chemokine sensing, and contribution of distinct signaling components to receptor activation and integrin conformations. Use of therapeutics modulating neutrophil activation responses as well as mutations causing dysfunctional neutrophil receptors and impaired signaling cascades have been defined in translational animal models. Human correlates of such mutations result in increased susceptibility to infections or organ damage. This review focuses on current advances in the understanding of the regulation of neutrophil recruitment and functionality and translational implications of current discoveries in the field with a focus on acute inflammation and sepsis.