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Heat‐killed Staphylococcus aureus reduces atherosclerosis by inducing anti‐inflammatory macrophages
Author(s) -
Frodermann V.,
Duijn J.,
Puijvelde G. H. M.,
Santbrink P. J.,
Lagraauw H. M.,
Vries M. R.,
Quax P. H. A.,
Bot I.,
Foks A. C.,
Jager S. C. A.,
Kuiper J.
Publication year - 2016
Publication title -
journal of internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.625
H-Index - 160
eISSN - 1365-2796
pISSN - 0954-6820
DOI - 10.1111/joim.12484
Subject(s) - medicine , staphylococcus aureus , microbiology and biotechnology , immunology , macrophage , bacteria , in vitro , biology , biochemistry , genetics
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 CCL 2 expression levels were significantly downregulated by on average 40%. HK ‐ SA ‐treated mice had reduced numbers of inflammatory Ly‐6C hi 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 ( TLR 2)‐dependent increase in IL ‐10, arginase‐1, iNOS , TNF ‐ α , PD ‐L1, CCL 22 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 TLR 2 and PI 3K, and protects against the development of atherosclerosis. Commensalism with S. aureus could thus reduce cardiovascular events.