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Endotoxin Tolerance in Abdominal Aortic Aneurysm Macrophages, In Vitro: A Case–Control Study
Journal article   Open access   Peer reviewed

Endotoxin Tolerance in Abdominal Aortic Aneurysm Macrophages, In Vitro: A Case–Control Study

Lara Meital, Mark Windsor, Alesiya Maynard, Karl Schulze, Rebecca Magee, Jill O'Donnell, Pankaj Jha, Chaim Y Meital, Maria-Christina Perissiou, Steven Coverdale, …
Antioxidants, Vol.9(9), pp.1-17
2020
DOI: https://doi.org/10.3390/antiox9090896
PMCID: PMC7554856
PMID: 32967278
Appears in  Cancer Research Cluster Research Collection
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https://doi.org/10.3390/antiox9090896View
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Abstract

abdominal aortic aneurysm endotoxin tolerance lipid rafts macrophages toll-like receptor 4 (TLR4)
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.

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