Background-Neutrophils (PMN) are the primary leukocyte responders during acute inflammation. After migrating into the tissues, PMN undergo programmed cell death (apoptosis) and are subsequently removed via phagocytosis by resident macrophages during the resolution phase. Efficient phagocytosis of apoptotic neutrophils is necessary for successful resolution. CD47 plays a critical role in mediating the phagocytic response, although its role in the phagocytosis of apoptotic PMN in incompletely understood.
Neonatal PMN (polymorphonuclear neutrophils) exhibit altered inflammatory responsiveness and greater longevity compared with adult PMN; however, the involved mechanisms are incompletely defined. Receptors containing immunoreceptor tyrosine-based inhibitory motif (ITIM) domains promote apoptosis by activating inhibitory phosphatases, such as Src homology domain 2-containing tyrosine phosphatase-1 (SHP-1), that block survival signals. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9, an immune inhibitory receptor with an ITIM domain, has been shown to induce cell death in adult PMN in association with SHP-1. To test our hypothesis that neonatal PMN inflammatory function may be modulated by unique Siglec-9 and SHP-1 interactions, we compared expression of these proteins in adult and neonatal PMN. Neonatal PMN exhibited diminished cellular expression of Siglec-9, which was phosphorylated in the basal state. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment decreased Siglec-9 phosphorylation levels in neonatal PMN but promoted its phosphorylation in adult PMN, observations associated with altered survival signaling. Although SHP-1 expression was also diminished in neonatal PMN, GM-CSF treatment had minimal effect on phosphorylation status. Further analysis revealed that Siglec-9 and SHP-1 physically interact, as has been observed in other immune cells. Our data suggest that age-specific interactions between Siglec-9 and SHP-1 may influence the altered inflammatory responsiveness and longevity of neonatal PMN. invasion and contribute to the clearance of pathogens. During resolution of the inflammatory process, neutrophils undergo apoptosis and are removed through ingestion by resident macrophages (1,2). However, a delay in the clearance of activated neutrophils promotes their persistence in tissues, a contributing factor in the pathogenesis of a variety of chronic inflammatory conditions (3). We reported a prolonged survival of neonatal neutrophils with enhanced inflammatory and cytotoxic activity (4,5). Altered inflammatory responses and delayed apoptosis may contribute to a variety of chronic inflammatory disorders in neonates, including bronchopulmonary dysplasia (6 -8). Understanding the mechanisms modulating neonatal neutrophil responses to inflammation is therefore paramount in designing targeted therapeutic approaches.Neonatal neutrophils have an intrinsic resistance to spontaneous and Fas-mediated apoptosis associated with decreased expression of proapoptotic proteins (4,9,10); however, the underlying mechanisms remain unclear. Compromise of this neutrophil function in neonates suggests a dysregulation of mechanisms important to inflammation and its resolution. Normally, the initiation and termination of inflammatory processes are tightly regulated through a combination of activating and inhibitory signals (11). An imbalance in this regulation could result in prolongation of processes that induce tissue damage and neutrophil reactivation, setting the stage for chronic infla...
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