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

Meital, Lara T., Windsor, Mark T., Maynard, Alesiya E., Schulze, Karl, Magee, Rebecca, O'Donnell, Jill, Jha, Pankaj, Meital, Chaim Y., Perissiou, Maria, Coverdale, Steven, Golledge, Jonathan, Kuballa, Anna V., Bailey, Tom G., Askew, Christopher D., and Russell, Fraser D. (2020) Endotoxin tolerance in abdominal aortic aneurysm macrophages, in vitro: a case-control study. Antioxidants, 9 (9). 896.

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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.

Item ID: 66822
Item Type: Article (Research - C1)
ISSN: 2076-3921
Keywords: abdominal aortic aneurysm; endotoxin tolerance; lipid rafts; macrophages; toll-like receptor 4 (TLR4).
Copyright Information: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Funders: Wishlist—Sunshine Coast Health Foundation, University of the Sunshine Coast (USC), National Health and Medical Research Council (NHMRC), Queensland Government (QG)
Projects and Grants: NHMRC practitioner fellowship 1117061, QG Senior Clinical Research Fellowship
Date Deposited: 02 Mar 2021 22:25
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320199 Cardiovascular medicine and haematology not elsewhere classified @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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