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MPLA inhibits release of cytotoxic mediators from human neutrophils while preserving efficient bacterial killing

Lookup NU author(s): Dr Marie Ruchaud-Sparagano, Jonathan Scott, Professor John Simpson

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Abstract

Monophosphoryl lipid A (MPLA) is a lipopolysaccharides (LPS) derivative associated with neutrophil-dependent anti-inflammatory outcomes in animal models of sepsis. Little is known about the effect of MPLA on neutrophil function. This study sought to test the hypothesis that MPLA would reduce release of cytotoxic mediators from neutrophils without impairing bacterial clearance. Neutrophils were isolated from whole blood of healthy volunteers. The effects of MPLA and LPS on autologous serum-opsonised Pseudomonas aeruginosa killing by neutrophils and phagocytosis of autologous serum-opsonised zymosan were examined. Neutrophil oxidative burst, chemotaxis, enzyme and cytokine release as well as Toll-like receptor 4 (TLR4) expression were assessed following exposure to LPS or MPLA. LPS, but not MPLA, induced significant release of superoxide and myeloperoxidase from neutrophils. However, MPLA did not impair neutrophil capacity to ingest microbial particles and kill P. aeruginosa efficiently. MPLA was directly chemotactic for neutrophils, involving TLR4, p38 mitogen-activated protein kinase and tyrosine and alkaline phosphatases. LPS, but not MPLA, impaired N-formyl-methionyl-leucyl phenylalanine-directed migration of neutrophils, increased surface expression of TLR4, increased interleukin-8 release and strongly activated the myeloid differentiation primary response 88 pathway. Phosphoinositide 3-kinase inhibition significantly augmented IL-8 release from MPLA-treated neutrophils. The addition of MPLA to LPS-preincubated neutrophils led to a significant reduction in LPS-mediated superoxide release and TLR4 surface expression. Collectively, these findings suggest that MPLA directs efficient chemotaxis and bacterial killing in human neutrophils without inducing extracellular release of cytotoxic mediators and suggest that MPLA warrants further attention as a potential therapeutic in human sepsis.


Publication metadata

Author(s): Ruchaud-Sparagano MH, Mills R, Scott J, Simpson AJ

Publication type: Article

Publication status: Published

Journal: Immunology and Cell Biology

Year: 2014

Volume: 92

Issue: 9

Pages: 799-809

Print publication date: 01/10/2014

Online publication date: 08/07/2014

Acceptance date: 04/06/2014

ISSN (print): 0818-9641

ISSN (electronic): 1440-1711

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/icb.2014.55

DOI: 10.1038/icb.2014.55


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