sanguinis have been detected in clinical specimens of atheromatous plaque (Chiu, 1999; Nakano et al., 2006; Koren et al., 2011). Moreover, foam cell formation was accelerated by heat-inactivated S. sanguinis

as well as viable bacteria (Fig. 1). Activation of macrophages by bacterial components such as LPS has been reported to be sufficient to induce foam cell formation (Funk et al., 1993; Kakayoglu & Byrne, 1998). Based on recent understanding of atherosclerosis as an inflammatory disease (Erridge, 2008), our results suggest that both live and dead S. sanguinis may be potential atherogenic LGK-974 manufacturer stimuli, as each were shown to be promoters of inflammatory foam cell formation. Although the periodontal pathogen P. gingivalis is known to induce

foam cell formation (Giacona et al., 2004; Qi et al., 2003), our literature search indicated that the involvement of oral streptococci in foam cell formation has not been reported. Thus, the molecular mechanism by which S. sanguinis induces foam cell formation requires Target Selective Inhibitor Library order further investigation. Our subsequent experiment revealed that infection with viable S. sanguinis at higher doses (MOI > 100) induced cell death of differentiated THP-1 macrophages (Fig. 2). Induction of cell death of macrophages may contribute to atherosclerosis, because several investigations have suggested that dead macrophages are involved in the development of atherosclerosis plaque (Tabas, 2010). Therefore, S. sanguinis is potentially able to stimulate eltoprazine the progression of atherosclerosis by inducing cell death of macrophages, as well as by stimulating foam cell formation. Recent investigations have reported that several pathogenic streptococci and staphylococci induce cell

death of macrophages (Fettucciari et al., 2000; Craven et al., 2009; Harder et al., 2009). Those studies suggested that bacterial pore-inducing toxins such as streptolysin O, β-hemolysin and α-hemolysin trigger the cell death of infected macrophages. As S. sanguinis has no pore-forming toxins, our finding that S. sanguinis-induced cell death of macrophages was unexpected. Therefore, we examined the possible involvement of the cell death pathway in phagocytic cells. The initial recognition of microorganisms is mediated by pattern recognition receptors such as toll-like receptors, which recognize bacterial components (Ishii et al., 2008). Another class of pattern recognition receptors, intracellular nucleotide-binding oligomerization receptors (NLRs), have been identified (Ishii et al., 2008). A group of NLRs participates in the formation of protein complexes called inflammasomes, which mediate the induction of caspase-1 activation in response to microbial stimulation (Yu & Finlay, 2008; Schroder & Tschopp, 2010). In the present study, we found that S. sanguinis infection induced the secretion of IL-1β and ATP (Fig. 4), which are known to be implicated in activation of inflammasomes (Petrilli et al., 2007).