Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury

Shaoning Jiang, Dae Won Park, Jean Marc Tadie, Murielle Gregoire, Jessy Deshane, Jean Francois Pittet, Edward Abraham, Jaroslaw W. Zmijewski

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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 AMPactivated 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.

Original languageEnglish
Pages (from-to)4795-4803
Number of pages9
JournalJournal of Immunology
Volume192
Issue number10
DOIs
Publication statusPublished - 2014 May 15

ASJC Scopus subject areas

  • Immunology

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