Abstract
Neutrophil activation and adhesion must be tightly controlled to prevent complications associated with excessive inflammatory responses. The role of the anti-inflammatory peptide chemerin15 (C15) and the receptor ChemR23 in neutrophil physiology is unknown. Here, we report that ChemR23 is expressed in neutrophil granules and rapidly upregulated upon neutrophil activation. C15 inhibits integrin activation and clustering, reducing neutrophil adhesion and chemotaxis in vitro. In the inflamed microvasculature, C15 rapidly modulates neutrophil physiology inducing adherent cell detachment from the inflamed endothelium, while reducing neutrophil recruitment and heart damage in a murine myocardial infarction model. These effects are mediated through ChemR23. We identify the C15/ChemR23 pathway as a new regulator and thus therapeutic target in neutrophil-driven pathologies.
Highlights
In vertebrates, tissue trauma, infection and ischaemia–reperfusion injury prompt rapid neutrophil extravasation from the circulation to the site of injury [1]
Using flow cytometry we found that ChemR23 is expressed on 68% of resting human neutrophils (Fig 1A,B)
Neutrophil ChemR23 expression rapidly increased upon stimulation with pro-inflammatory mediators, tumor necrosis factor alpha (TNFa), fMLF and interleukin-8 or exposure of isolated neutrophils to activated endothelial cells under flow, but was unaffected by antiinflammatory mediators
Summary
Tissue trauma, infection and ischaemia–reperfusion injury prompt rapid neutrophil extravasation from the circulation to the site of injury [1]. Integrin pro-adhesive activity can be increased by clustering, whereby the integrin accumulates in discrete areas of the plasma membrane [2] Interaction of these activated b2 integrins with their respective ligands results in neutrophil adhesion, followed by intravascular crawling. Higher organisms have evolved a network of anti-inflammatory and pro-resolving pathways, which counter-regulate inflammatory responses and promote regain of tissue homeostasis, ensuring that the inflammatory response is limited in magnitude, time and space. Improved understanding of these endogenous regulatory systems could pave the way for the development of therapeutic approaches to tame inflammatory pathologies [8,9]. C15 appears to achieve these effects by fine-tuning neutrophil–endothelial cell interactions through modulation of b2 integrin activation (affinity) and clustering (avidity) and L-selectin shedding
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