Trends in Immunology
ReviewInnate immune cell traffickingNeutrophils cascading their way to inflammation
Section snippets
Ostensibly redundant role of chemoattractants in recruitment of neutrophils
Neutrophils are essential effector cells of the innate immune response, forming the first line of defense against bacterial and fungal pathogens. The engulfment of pathogens and the release of reactive oxygen species (ROS) and proteases contribute to the key role of neutrophils in host defense [1]. Accordingly, neutropenia is an alarming condition that renders patients susceptible to fulminant, life-threatening infections. However, neutrophils also contribute significantly to tissue damage in
Decision point I: trafficking from bone marrow into peripheral blood
Neutrophils are the most abundant immune cell type. It is estimated that each day 5 × 1010–10 × 1010 new neutrophils are formed in the bone marrow [15]. A neutrophil spends the majority of its life in the bone marrow: under physiological conditions, <2% of neutrophils are found in the bloodstream [16]. In the latter location, neutrophils have a short half life (∼6–8 h in humans and ∼11 h in mice) 15, 17. Neutrophil homeostasis in peripheral blood is tightly regulated primarily as a consequence of:
Decision point II: entering peripheral tissues or not
Neutrophils in the peripheral blood can be rapidly recruited into peripheral tissues in the event of pathogenic invasion or sterile tissue damage. The disturbance of tissue homeostasis is recognized either by professional tissue-resident sentinel cells, such as macrophages and mast cells, or by stromal cells 26, 27. A panel of diverse stimuli, especially pathogen-associated molecular pattern (PAMPs) and damage-associated molecular pattern (DAMPs) molecules, activates these sentinel cells to
Decision point III: finding the cue into the inflammatory site
It has recently been shown that diverse chemoattractants can act in a sequential cascade to recruit neutrophils into an inflammatory site. In this case, immune-complex-induced arthritis (K/BxN serum transfer-induced arthritis) is driven by a lipid–cytokine–chemokine cascade, precisely by leukotriene (LT)B4–IL-1β–CC chemokine receptor (CCR)1/CXCR2 ligands [13]. LTB4 and its high-affinity receptor BLT1 are absolutely required for the induction of immune-complex-induced arthritis. In this model,
Self-perpetuation through neutrophils recruiting neutrophils
Neutrophils have been regarded as purely phagocytotic effector cells, lacking the noteworthy capability to synthesize proteins once they are terminally differentiated. However, it has become evident that neutrophils in peripheral tissues are more active transcriptionally and translationally than their counterparts in the blood, and that they contribute to the orchestration of inflammatory reactions by releasing chemokines, cytokines and lipid mediators 29, 63, 64. Although the quantity of
Conclusions and future directions
In recent years, temporal and spatial cascades of chemically diverse chemoattractants have been identified that coordinate the recruitment of neutrophils in mouse models of acute local inflammation. These findings suggest chemoattractants have unique roles in vivo. Temporal and spatial cascades of chemoattractants appear to be necessary to guide the complex migratory path of neutrophils from the bone marrow into the blood, from the blood into the tissue, and then once in the tissue, guide
Acknowledgments
This work was supported by grants of the Deutsche Forschungsgemeinschaft (Sa1960/1-1 to C.D.S.) and of the National Institutes of Health (R01-AI050892 to A.D.L. and K08-AR054094 to N.D.K.).
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