Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin‐8 and leukotriene B₄ receptors

Abstract

SummaryNeutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B 4 (LTB 4 ) constitute key mediators by binding to the surface receptors CXCR1/2 and BLT1, respectively. Oligonucleotides (ODN) containing CpG motifs mediate potent immunomodulatory effects through binding to Toll-like receptor 9. So far, knowledge on how ODN can affect neutrophil migration during inflammation is lacking. This study demonstrates that several novel CpG ODN significantly down-regulate the surface expression of CXCR1/2 and BLT1. In addition, the ODN significantly blocked IL-8-induced and LTB 4 -induced neutrophil migration in vitro, as well as leucocyte migration in vivo demonstrated in mice by intravital microscopy and in a model of airway inflammation. The down-regulation of CXCR1 is rapid, occurring 15 min after ODN stimulation, and can be mediated through an endosomally independent mechanism. Inhibition of the IL-8 and LTB 4 pathways may provide new opportunities of therapeutic intervention using ODN to reduce neutrophil infiltration during inflammation.

Biogenic selenium nanoparticles: characterization, antimicrobial activity and effects on human dendritic cells and fibroblasts

“…We then investigated whether SeNPs stimulate DCs to release of pro‐inflammatory and immunostimulatory cytokines (particularly those involved in the activation of inflammatory and immune responses), such as IL‐12 which stimulates natural killer cells and T lymphocytes (Vignali and Kuchroo, ), IL‐8 which causes leucocyte chemotaxis and activation (Admyre et al ., ), as well as IL‐6 and TNF‐α which elicit inflammation and the systemic acute phase reaction, characterized by fever, headache, anorexia, nausea, emesis and changes in the sleep–wake cycle (Elmquist et al ., ; Suffredini et al ., ).…”

Leukotriene B4 indicates lung injury and on-going inflammatory changes after severe trauma in a porcine long-term model

“…As rationale for an increased neutrophil accumulation via IL-8, it has been demonstrated that IL-8 might be directly involved in post-traumatic pulmonary inflammatory processes by attracting PMN to the lung [13]. More recently, it has been shown that down-regulating the surface expression of the IL-8 receptors CXCR1/2 significantly blocked IL-8-induced neutrophil migration in vitro and in vivo in a model of pulmonary inflammation [29]. Other biomarkers of inflammatory pulmonary complications after trauma as IL-1β, IL-10 and IL-18 did not show significant changes (Fig.…”

“…Recently, in vivo imaging has revealed that LTB4 is required for neutrophil swarming in the extravascular space of a damaged tissue [28]. Moreover, down-regulating the surface expression of CXCR1/2 and BLT1 (receptors for IL-8 and LTB4), significantly blocked IL-8-induced and LTB4-induced neutrophil migration in vitro and in vivo as demonstrated in mice by intravital microscopy in a model of airway inflammation [29].…”

Characterisation of the Whole Blood mRNA Transcriptome in Holstein-Friesian and Jersey Calves in Response to Gradual Weaning

“…For example, there was decreased transcription of LTB4R , the gene coding for the leukotriene B4 receptor which functions in the induction of chemotaxis following ligand binding, in J relative to H-F, at all time-points relative to weaning. It is an important mediator of the inflammatory immune response as it is involved in the recruitment of pro-inflammatory cells (including neutrophils [ 43 ] macrophages, eosinophils, mast cells, dendritic cells and effector T cells [ 44 ]) to sites of infection [ 45 ]. Additionally, genes involved in the cellular killing activity of natural killer and cytotoxic T cells were transcriptionally decreased in Jersey calves at all time-points.…”