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.
Highlights
Abdominal aortic aneurysm (AAA), characterized by a complex, multifactorial pathogenesis, is a clinically silent vascular disease typically localized to the terminal aortic segment [1]
Concentrations of IL-6 (Figure 1c), Transforming growth factor-β (TGF-β) (Figure 1d) and matrix metalloproteinase-9 (MMP-9) (Figure 1e) in abdominal aortic aneurysm (AAA) plasma were comparable to the control cohort
Gram negative bacteria [31], cleaved extracellular matrix components [32] or an increased circulating concentration of fibrinogen [33], provide a level of endogenous danger signaling sufficient to prime macrophage Toll-like receptor 4 (TLR4) towards an endotoxin tolerant state. In line with this hypothesis, our study provides the first evidence that AAA macrophages exhibit a refractory phenotype characterized by suppressed production of inflammatory cytokines, oxidative stress biomarkers and elastolytic enzymes following LPS challenge
Summary
Abdominal aortic aneurysm (AAA), characterized by a complex, multifactorial pathogenesis, is a clinically silent vascular disease typically localized to the terminal aortic segment [1]. Degenerative by nature, the condition is associated with chronic inflammatory cell infiltration and destructive remodeling of aortic connective tissue that culminates in a focal loss of vessel wall integrity and full thickness dilation of the abdominal aorta [2,3]. AAA initiation and progression is strongly associated with aortic macrophage accumulation [4]. Macrophages, derived from circulating monocytes or monocyte reservoirs in the spleen, are phagocytic immune cells with an ability to assume distinct polarization states in response to environmental stimuli [5]. An examination of macrophage cell surface markers in human aneurysmal infrarenal aortic wall sections demonstrated that M1 macrophages are predominant in the aortic adventitia while Polarization of macrophages extends along a continuum of diverse phenotypes with the extreme ends (classically activated pro-inflammatory M1 macrophages and alternatively activated anti-inflammatory M2 macrophages) most commonly recognized [6].
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