STAT5 Is an Ambivalent Regulator of Neutrophil Homeostasis

BACKGROUND: Although STAT5 promotes survival of hematopoietic progenitors, STAT5-/- mice develop mild neutrophilia. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that in STAT5-/- mice, liver endothelial cells (LECs) autonomously secrete high amounts of G-CSF, allowing myeloid progenitors to overcompensate for their intrinsic survival defect. However, when injected with pro-inflammatory cytokines, mutant mice cannot further increase neutrophil production, display a severe deficiency in peripheral neutrophil survival, and are therefore unable to maintain neutrophil homeostasis. In wild-type mice, inflammatory stimulation induces rapid STAT5 degradation in LECs, G-CSF production by LECs and other cell types, and then sustained mobilization and expansion of long-lived neutrophils. CONCLUSION: We conclude that STAT5 is an ambivalent factor. In cells of the granulocytic lineage, it exerts an antiapoptotic function that is required for maintenance of neutrophil homeostasis, especially during the inflammatory response. In LECs, STAT5 negatively regulates granulopoiesis by directly or indirectly repressing G-CSF expression. Removal of this STAT5-imposed brake contributes to induction of emergency granulopoiesis.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Regulating immunity to malaria.

The optimal outcome of a malaria infection is that parasitized cells are killed and degraded without inducing significant pathology. Since much of the pathology of malaria infection can be immune-mediated, this implies that immune responses have to be carefully regulated. The mechanisms by which anti-malarial immune responses are believed to be regulated were discussed at the recent Malaria Immunology Workshop (Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; February 2005). Potential regulatory mechanisms include regulatory T cells, which have been shown to significantly modify cellular immune responses to various protozoan infections, including leishmania and malaria; neutralising antibodies to pro-inflammatory malarial toxins such as glycosylphosphatidylinositol and haemozoin; and self-regulating networks of effector molecules. Innate and adaptive immune responses are further moderated by the broader immunological environment, which is influenced by both the genetic background of the host and by co-infection with other pathogens. A detailed understanding of the interplay between these different immunoregulatory processes may facilitate the rationale design of vaccines and novel therapeutics