Response of Neutrophils to Extracellular Haemoglobin and LTA in Human Blood System.

Abstract

BACKGROUND:

Haemolytic infection lyses red blood cells, releasing haemoglobin (Hb) into the plasma. Although recent studies showed that immune cells recognize redox-active cytotoxic extracellular Hb (metHb) bound to pathogen-associated molecular patterns (PAMPs), currently available information is limited to experiments performed in defined conditions using single cell lines. Therefore, a systemic approach targeting primary whole blood cells is required to better understand the cellular immune defence against metHb and PAMPs, when under a haemolytic infection.

METHODS:

We investigated how human white blood cells, including neutrophils, respond to metHb and lipoteichoic acid (LTA) by measuring reactive oxygen species (ROS), signalling mediators (ERK and p38), NF-κB, cytokines, elastase secretion and cell activation markers.

FINDINGS:

metHb activates NF-κB in TLR2-expressing HEK293 cells but not in normal or TLR9-expressing HEK293 cells. Treatment of isolated neutrophils with metHb increased production of ROS and expressions of IL-8, TNFα, and CD11b, which were further enhanced by metHb + LTA complex. While LTA stimulated the survival of neutrophils, it caused apoptotic cell death when complexed with metHb. The activation of neutrophils by metHb + LTA was subdued by the presence of other types of white blood cells.

INTERPRETATION:

metHb and metHb + LTA complex are ligands of TLR2, inducing an unconventional TLR signalling pathway. Neutrophils are a highly sensitive cell type to metHb + LTA complex. During a haemolytic infection, white blood cells in the vicinity crosstalk to modulate neutrophil TLR-signalling induced by metHb and LTA.

• Authors: Sae-Kyung Lee, Suh Yee Goh, Yuan Qi Wong, Jeak Ling Ding
• Journal: EBioMedicine (EBioMedicine) Vol. 2 Issue 3 Pg. 225-33 (Mar 2015) ISSN: 2352-3964 [Print] Netherlands
• PMID: 26137562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Lipopolysaccharides
• NF-kappa B
• Pathogen-Associated Molecular Pattern Molecules
• TLR2 protein, human
• Teichoic Acids
• Toll-Like Receptor 2
• lipoteichoic acid
• Methemoglobin
• Pancreatic Elastase

Topics

• Cell Death (drug effects)
• Cell Survival (drug effects)
• Cytokines (metabolism)
• HEK293 Cells
• Humans
• Inflammation (immunology, pathology)
• Leukocytes (drug effects, metabolism)
• Lipopolysaccharides (metabolism, pharmacology)
• Methemoglobin (metabolism, pharmacology)
• NF-kappa B (metabolism)
• Neutrophil Activation (drug effects, physiology)
• Pancreatic Elastase (metabolism)
• Pathogen-Associated Molecular Pattern Molecules (metabolism)
• Signal Transduction
• Teichoic Acids (metabolism, pharmacology)
• Toll-Like Receptor 2 (genetics, immunology, metabolism)