Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury.
Although resistin was recently found to modulate insulin resistance in preclinical models of type II diabetes and obesity, recent studies also suggested that resistin has proinflammatory properties. We examined whether the human-specific variant of resistin affects neutrophil activation and the severity of LPS-induced acute lung injury. Because human and mouse resistin have distinct patterns of tissue distribution, experiments were performed using humanized resistin mice that exclusively express human resistin (hRTN(+/-)(/-)) but are deficient in mouse resistin. Enhanced production of TNF-α or MIP-2 was found in LPS-treated hRtn(+/-/-) neutrophils compared with control Rtn(-/-/-) neutrophils. Expression of human resistin inhibited the activation of AMP-activated protein kinase, a major sensor and regulator of cellular bioenergetics that also is implicated in inhibiting inflammatory activity of neutrophils and macrophages. In addition to the ability of resistin to sensitize neutrophils to LPS stimulation, human resistin enhanced neutrophil extracellular trap formation. In LPS-induced acute lung injury, humanized resistin mice demonstrated enhanced production of proinflammatory cytokines, more severe pulmonary edema, increased neutrophil extracellular trap formation, and elevated concentration of the alarmins HMGB1 and histone 3 in the lungs. Our results suggest that human resistin may play an important contributory role in enhancing TLR4-induced inflammatory responses, and it may be a target for future therapies aimed at reducing the severity of acute lung injury and other inflammatory situations in which neutrophils play a major role.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
Shaoning
S
Jiang
Dae Won
DW
Park
Jean-Marc
JM
Tadie
Murielle
M
Gregoire
Jessy
J
Deshane
Jean Francois
JF
Pittet
Edward
E
Abraham
Jaroslaw W
JW
Zmijewski
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D000818:Animals; D054426:Chemokine CXCL2 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D052243:Resistin / Q000235:genetics / Q000276:immunology*; D012720:Severity of Illness Index; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D006657:Histones; D008070:Lipopolysaccharides; C499624:RETN protein, human; D052243:Resistin; C499623:Retn protein, mouse; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D055372:AMP-Activated Protein Kinases