Abstract
Background: Macrophages contribute to inflammatory processes occurring within the aortic wall of patients with abdominal aortic aneurysm (AAA). Macrophage function is modulated by endogenous regulatory mechanisms that include endotoxin tolerance, a phenomenon linked to aberrant Toll-like receptor 4 (TLR4) signalling. Since AAA is associated with the presence of known TLR4 activators, this study investigated the possibility that AAA macrophages exhibit an immunosuppressive phenotype reminiscent of tolerance.
Methods and Results: Macrophages were isolated from whole blood of patients with small (3.0–4.5 cm) AAA (n = 33) and age-matched and sex-matched control participants (n = 44). Levels of TNF-α and the oxidative stress biomarker 8-isoprostane were elevated in plasma from AAA patients (TNF-α 26.0 ± 6.8 vs 5.6 ± 1.3 pg/mL, p < 0.001; 8-isoprostane 52.0 ± 3.5 vs 37.0 ± 3.6 pg/mL, p < 0.05) and activity levels of the antioxidant enzyme catalase were lower (43.1 ± 6.2 vs 75.7 ± 7.1 pmol.minute/αg protein, p < 0.01), consistent with systemic inflammation and oxidative stress. In contrast, lipopolysaccharide-stimulated secretion of IL-6, TNF-α and 8-isoprostane in cultured AAA macrophage supernatants was markedly lower compared to control participants, a finding congruent with endotoxin tolerance. Metabolite levels of PGE2, a mediator that directs inflammation toward resolution pathways, were consistently lower in plasma from AAA patients (15.22 ± 1.2 pg/mL) compared to the control cohort (20.4 ± 1.4 pg/mL; p < 0.01).
Conclusion: The inflamed, AAA. oxidised microenvironment favoured macrophages with an endotoxin tolerant-like phenotype characterised by a diminished capacity to produce proinflammatory mediators that enhance the immune response. Diminished immune capacity in AAA may exacerbate the persistent inflammation underlying this disease state and thereby contribute to failure of resolution.
Methods and Results: Macrophages were isolated from whole blood of patients with small (3.0–4.5 cm) AAA (n = 33) and age-matched and sex-matched control participants (n = 44). Levels of TNF-α and the oxidative stress biomarker 8-isoprostane were elevated in plasma from AAA patients (TNF-α 26.0 ± 6.8 vs 5.6 ± 1.3 pg/mL, p < 0.001; 8-isoprostane 52.0 ± 3.5 vs 37.0 ± 3.6 pg/mL, p < 0.05) and activity levels of the antioxidant enzyme catalase were lower (43.1 ± 6.2 vs 75.7 ± 7.1 pmol.minute/αg protein, p < 0.01), consistent with systemic inflammation and oxidative stress. In contrast, lipopolysaccharide-stimulated secretion of IL-6, TNF-α and 8-isoprostane in cultured AAA macrophage supernatants was markedly lower compared to control participants, a finding congruent with endotoxin tolerance. Metabolite levels of PGE2, a mediator that directs inflammation toward resolution pathways, were consistently lower in plasma from AAA patients (15.22 ± 1.2 pg/mL) compared to the control cohort (20.4 ± 1.4 pg/mL; p < 0.01).
Conclusion: The inflamed, AAA. oxidised microenvironment favoured macrophages with an endotoxin tolerant-like phenotype characterised by a diminished capacity to produce proinflammatory mediators that enhance the immune response. Diminished immune capacity in AAA may exacerbate the persistent inflammation underlying this disease state and thereby contribute to failure of resolution.
| Original language | English |
|---|---|
| Pages (from-to) | S348 |
| Number of pages | 1 |
| Journal | Heart, Lung and Circulation |
| Volume | 27 |
| Issue number | Supplement 2 |
| DOIs | |
| Publication status | Published - 28 Jul 2018 |
| Event | 66th Cardiac Society of Australia and New Zealand Annual Scientific Meeting, the International Society for Heart Research Australasian Section Annual Scientific Meeting and the 12th Annual Australia and New Zealand Endovascular Therapies Meeting - Brisbane, Australia Duration: 2 Aug 2018 → 5 Aug 2018 |