RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 14 March 2014; doi:10.1038/nri3648
NEUTROPHILS
Nanoparticles targeting the bad guys
Eugenio Franchi/Alamy
The recruitment of circulating neutrophils to the site of infection is crucial to eliminate invading pathogens, but excessive accumulation of neutrophils at these sites can result in tissue damage and inflammatory disease. Reporting in Nature Nanotechnology, Wang et al. now show that nanoparticles loaded with anti-inflammatory drugs can specifically target activated neutrophils, without affecting the bactericidal activity of circulating neutrophils. Using real-time fluorescence intravital microscopy, the authors studied the ability of neutrophils to take up albumin nanoparticles
indicates a role for FcγR signalling in the neutrophil uptake of albumin nanoparticles
made from denatured albumin and with incorporated fluorescent dyes. Tumour necrosis factor was injected into the scrotum of mice to induce vascular inflammation and albumin nanoparticles were injected intra venously 3 hours post-challenge. The majority of albumin nanoparticles were internalized by neutrophils that were adherent to the venular endothelial cells; colocalization experiments showed that only adherent neutrophils internalized the albumin nanoparticles, whereas circulating neutrophils did not. Next, the authors investigated how nanoparticles could specifically target activated neutrophils. As Fc receptors for IgG (FcγRs) are predominantly expressed on the surface of activated adherent neutrophils, compared with circulating neutrophils, the role of FcγR signalling was investigated. The uptake of albumin nanoparticles was reduced by ~50% in neutrophils from Fcgr3–/– mice, compared with neutro phils from wild-type mice. This indicates a role for FcγRIII signalling in the uptake of albumin nanoparticles by activated neutrophils. The mechanism for the residual uptake is unclear but it is possible that other FcγRs are involved. Previous studies have shown that inhibition of β2 integrins can block the adhesion of neutrophils to endothelial cells and prevent inflammation, but such antibodies affect all neutrophils and thus reduce their bactericidal activity. To investigate the therapeutic potential of albumin nanoparticles, the authors loaded them with piceatannol, an inhibitor of the tyrosine-protein
NATURE REVIEWS | IMMUNOLOGY
kinase SYK, which is important for β2 integrin-mediated adhesion and migration of neutrophils. Interestingly, the administration of piceatannol-loaded albumin nanoparticles greatly reduced the number of adherent neutrophils and increased the frequency of rolling cells, whereas albumin nanoparticles alone had no effect. Hence, piceatannol-loaded nanoparticles were specifically internalized by activated neutrophils, and the interference of piceatannol with SYK signalling decreased the adherence of neutrophils and promoted their re-entry into the bloodstream. Finally, the authors addressed whether piceatannol-loaded nanoparticles could reduce the excessive neutrophil infiltration that occurs during the pathogenesis of acute lung injury. Indeed, mice injected intraperitoneally with lipopolysaccharide and treated with piceatannol-loaded albumin nanoparticles 2 hours postchallenge showed decreased infiltration of neutrophils into the lungs, compared with untreated mice. Furthermore, the authors found that piceatannol-loaded nanoparticles were far more effective than piceatannol administered as a free drug. This study highlights the potential of nanoparticles to deliver drugs in a highly precise manner to activated immune cells. This technology could potentially be applied to the treatment of a broad range of inflammatory diseases. Elisabeth Kugelberg ORIGINAL RESEARCH PAPER Wang, Z. et al. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nature Nanotechnol. 9, 204–210 (2014)
VOLUME 14 | APRIL 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEUTROPHILS
Nanoparticles targeting the bad guys
Eugenio Franchi/Alamy
The recruitment of circulating neutrophils to the site of infection is crucial to eliminate invading pathogens, but excessive accumulation of neutrophils at these sites can result in tissue damage and inflammatory disease. Reporting in Nature Nanotechnology, Wang et al. now show that nanoparticles loaded with anti-inflammatory drugs can specifically target activated neutrophils, without affecting the bactericidal activity of circulating neutrophils. Using real-time fluorescence intravital microscopy, the authors studied the ability of neutrophils to take up albumin nanoparticles
indicates a role for FcγR signalling in the neutrophil uptake of albumin nanoparticles
made from denatured albumin and with incorporated fluorescent dyes. Tumour necrosis factor was injected into the scrotum of mice to induce vascular inflammation and albumin nanoparticles were injected intra venously 3 hours post-challenge. The majority of albumin nanoparticles were internalized by neutrophils that were adherent to the venular endothelial cells; colocalization experiments showed that only adherent neutrophils internalized the albumin nanoparticles, whereas circulating neutrophils did not. Next, the authors investigated how nanoparticles could specifically target activated neutrophils. As Fc receptors for IgG (FcγRs) are predominantly expressed on the surface of activated adherent neutrophils, compared with circulating neutrophils, the role of FcγR signalling was investigated. The uptake of albumin nanoparticles was reduced by ~50% in neutrophils from Fcgr3–/– mice, compared with neutro phils from wild-type mice. This indicates a role for FcγRIII signalling in the uptake of albumin nanoparticles by activated neutrophils. The mechanism for the residual uptake is unclear but it is possible that other FcγRs are involved. Previous studies have shown that inhibition of β2 integrins can block the adhesion of neutrophils to endothelial cells and prevent inflammation, but such antibodies affect all neutrophils and thus reduce their bactericidal activity. To investigate the therapeutic potential of albumin nanoparticles, the authors loaded them with piceatannol, an inhibitor of the tyrosine-protein
NATURE REVIEWS | IMMUNOLOGY
kinase SYK, which is important for β2 integrin-mediated adhesion and migration of neutrophils. Interestingly, the administration of piceatannol-loaded albumin nanoparticles greatly reduced the number of adherent neutrophils and increased the frequency of rolling cells, whereas albumin nanoparticles alone had no effect. Hence, piceatannol-loaded nanoparticles were specifically internalized by activated neutrophils, and the interference of piceatannol with SYK signalling decreased the adherence of neutrophils and promoted their re-entry into the bloodstream. Finally, the authors addressed whether piceatannol-loaded nanoparticles could reduce the excessive neutrophil infiltration that occurs during the pathogenesis of acute lung injury. Indeed, mice injected intraperitoneally with lipopolysaccharide and treated with piceatannol-loaded albumin nanoparticles 2 hours postchallenge showed decreased infiltration of neutrophils into the lungs, compared with untreated mice. Furthermore, the authors found that piceatannol-loaded nanoparticles were far more effective than piceatannol administered as a free drug. This study highlights the potential of nanoparticles to deliver drugs in a highly precise manner to activated immune cells. This technology could potentially be applied to the treatment of a broad range of inflammatory diseases. Elisabeth Kugelberg ORIGINAL RESEARCH PAPER Wang, Z. et al. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nature Nanotechnol. 9, 204–210 (2014)
VOLUME 14 | APRIL 2014 © 2014 Macmillan Publishers Limited. All rights reserved
