Small abdominal aortic aneurysm is associated with endotoxin tolerant-like macrophage immunosuppression and decreased levels of the resolution-directed mediator PGE2

L. Meital, M. Windsor, A. Maynard, K. Schulze, R. Magee, J. O’Donnell, P. Jha, M. Perissiou, S. Coverdale, J. Golledge, T. Bailey, C. Askew, F. Russell

Research output: Contribution to journalMeeting Abstractpeer-review

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.

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