Endotoxin tolerance in abdominal aortic aneurysm macrophages, in vitro: a case–control study

Lara T. Meital, Mark T. Windsor, Alesiya E. Maynard, Karl Schulze, Rebecca Magee, Jill O’Donnell, Pankaj Jha, Chaim Y. Meital, Maria Perissiou, Steven Coverdale, Jonathan Golledge, Anna V. Kuballa, Tom G. Bailey, Christopher D. Askew, Fraser D. Russell

    Research output: Contribution to journalArticlepeer-review

    83 Downloads (Pure)

    Abstract

    Macrophages are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). This study examined the environmentally conditioned responses of AAA macrophages to inflammatory stimuli. Plasma- and blood-derived monocytes were separated from the whole blood of patients with AAA (30–45 mm diameter; n = 33) and sex-matched control participants (n = 44). Increased concentrations of pro-inflammatory and pro-oxidant biomarkers were detected in the plasma of AAA patients, consistent with systemic inflammation and oxidative stress. However, in monocyte-derived macrophages, a suppressed cytokine response was observed in AAA compared to the control following stimulation with lipopolysaccharide (LPS) (tumor necrosis factor alpha (TNF-α) 26.9 ± 3.3 vs. 15.5 ± 3.2 ng/mL, p < 0.05; IL-6 3.2 ± 0.6 vs. 1.4 ± 0.3 ng/mL, p < 0.01). LPS-stimulated production of 8-isoprostane, a biomarker of oxidative stress, was also markedly lower in AAA compared to control participants. These findings are consistent with developed tolerance in human AAA macrophages. As Toll-like receptor 4 (TLR4) has been implicated in tolerance, macrophages were examined for changes in TLR4 expression and distribution. Although TLR4 mRNA and protein expression were unaltered in AAA, cytosolic internalization of receptors and lipid rafts was found. These findings suggest the inflamed, pro-oxidant AAA microenvironment favors macrophages with an endotoxin-tolerant-like phenotype characterized by a diminished capacity to produce pro-inflammatory mediators that enhance the immune response.
    Original languageEnglish
    Article number896
    Number of pages17
    JournalAntioxidants
    Volume9
    Issue number9
    DOIs
    Publication statusPublished - 21 Sept 2020

    Keywords

    • abdomianl aortic aneurysm
    • endotoxin tolerance
    • lipid rafts
    • macrophages
    • toll-like receptor 4 (TLR4)

    Fingerprint

    Dive into the research topics of 'Endotoxin tolerance in abdominal aortic aneurysm macrophages, in vitro: a case–control study'. Together they form a unique fingerprint.

    Cite this