.Importance of Defining Pathways for Recruitment and Turnover of Leukocytes in Inflammation -Inflammation is an immune cell response that leads to the accumulation of white blood cells (leukocytes) at sites of infection, injury or irritation. The extravasation of polymorphonuclear leukocytes (PMNs), primarily neutrophils, through selectin and integrin-mediated pathways, to a site of inflammation is followed by the emigration of monocytes/macrophages (Fig. 1). Released granule proteins from activated neutrophils induce further emigration of inflammatory cells to such sites, involving selectins, P2-integrins and formyl-peptide receptors. Accompanying changes in the chemokine network create a favorable local microenvironment for extravasation of additional inflammatory monocytes. Thus, for this positive feedback loop to end, inflammation must be resolved by the removal of the inflammatory insult (bacteria or wound detritus), along with eventual removal of the emigrated inflammatory cells. While resolution is clearly the key to limiting tissue injury in all types of inflammation, it is remarkable that so little is known about the mechanism of cellular turnover and the factors promoting the resolution of inflammation. It has been thought that resolution occurs through spontaneous apoptosis of neutrophils and their subsequent phagocytosis and engulfment(4). Surprisingly, however, neutrophil apoptosis in vivo is not a major factor in regulating their numbers in inflammation. Unlike T cells, which accumulate following perturbation of pathways involved in leukocyte apoptosis(5,6), inhibition of neutrophil apoptosis does not greatly alter neutrophil turnover in vivo, but the mechanism(s) of targeting viable neutrophils for removal is unknown (5-8). Thus, neutrophil turnover is possibly regulated by nonapoptotic factors.

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