Heat-killed Staphylococcus aureus reduces atherosclerosis by inducing anti-inflammatory macrophages

• Autores: V. Frodermann, J. Kuiper, J. van Duijn, G.H. M. van Puijvelde, P.J. van Santbrink, H.M. Lagraauw, M.R. de Vries, P.H. A. Quax, S.C. A. de Jager, A.C. Foks, I. Bot
• Localización: Journal of Internal Medicine, ISSN-e 1365-2796, Vol. 279, Nº. 6, 2016, págs. 592-605
• Idioma: inglés
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• Resumen

  • Background Staphylococcus aureus cell wall components can induce IL-10 responses by immune cells, which may be atheroprotective. Therefore, in this study, we investigated whether heat-killed S. aureus (HK-SA) could inhibit the development of atherosclerosis.

    Methods Atherosclerosis-susceptible LDL receptor-deficient mice were administered intraperitoneal HK-SA twice weekly and fed a Western-type diet for 6 weeks.

    Results HK-SA administration resulted in a 1.6-fold increase in IL-10 production by peritoneal macrophages and splenocytes, and a 12-fold increase in serum IL-10 levels. Moreover, aortic plaque ICAM-1, VCAM-1 and CCL2 expression levels were significantly downregulated by on average 40%. HK-SA-treated mice had reduced numbers of inflammatory Ly-6Chi monocytes as well as Th1 and Th17 cells in the circulation and spleen, respectively. Attenuated leucocyte recruitment resulted in a significant inhibition of macrophage and T cell infiltration in atherosclerotic plaques, culminating in a significant 34% reduction in the development of atherosclerosis. To determine the effects of intraperitoneal HK-SA treatment, we stimulated macrophages with HK-SA in vitro. This resulted in a significant toll-like receptor 2 (TLR2)-dependent increase in IL-10, arginase-1, iNOS, TNF-α, PD-L1, CCL22 and indoleamine 2,3-dioxygenase expression. It was found that phosphoinositide 3-kinase crucially determined the balance of pro- and anti-inflammatory gene expression. The HK-SA-induced macrophage phenotype resembled M2b-like immunoregulatory macrophages.

    Conclusions We have shown that HK-SA treatment induces strong anti-inflammatory IL-10 responses by macrophages, which are largely dependent on TLR2 and PI3K, and protects against the development of atherosclerosis. Commensalism with S. aureus could thus reduce cardiovascular events.