Sphingosine 1–Phosphate Induces Antimicrobial Activity Both In Vitro and In Vivo

Abstract

Sphingosine 1-phosphate (S1P), a polar sphingolipid metabolite, is involved in a wide spectrum of biological processes, including Ca(++) mobilization, cell growth, differentiation, motility, and cytoskeleton organization. Here, we show a novel role of S1P in the induction of antimicrobial activity in human macrophages that leads to the intracellular killing of nonpathogenic Mycobacterium smegmatis and pathogenic M. tuberculosis. Such activity is mediated by host phospholipase D, which favors the acidification of mycobacteria-containing phagosomes. Moreover, when it was intravenously injected in mycobacteria-infected mice, S1P reduced mycobacterial growth and pulmonary tissue damage. These results identify S1P as a novel regulator of the host antimicrobial effector pathways.

Role of sphingosine-1-phosphate (S1P) and S1P receptor 2 in the phagocytosis of Cryptococcus neoformans by alveolar macrophages

“…Unlike previously published studies examining the effects of extracellular S1P on the antimicrobial actions of AMs against internalized Mycobacterium species ( Garg et al, 2004;Sali et al, 2009), treatment with S1P did not affect the intracellular growth of C. neoformans within AMs. This is not necessarily surprising since C. neoformans, in contrast with Mycobacterium, does not actively prevent the acidification or maturation of the phagosome (Feldmesser et al, 2000; Levitz et al, 1999), a process that in Mycobacterium-infected AMs is indeed controlled by S1P (Garg et al, 2004;Kusner, 2005;Malik et al, 2000; Thompson et al, 2005).…”

“…This is not necessarily surprising since C. neoformans, in contrast with Mycobacterium, does not actively prevent the acidification or maturation of the phagosome (Feldmesser et al, 2000; Levitz et al, 1999), a process that in Mycobacterium-infected AMs is indeed controlled by S1P (Garg et al, 2004;Kusner, 2005;Malik et al, 2000; Thompson et al, 2005). In addition, C. neoformans possesses virulence factors enabling internalized C. neoformans cells to survive within this microbicidal intracellular environment (Cox et al, 2001Shea et al, 2006;Wright et al, 2007;Zaragoza et al, 2008).…”

“…For instance, in studies examining the extrinsic effects of S1P on AMs (Garg et al, 2004(Garg et al, , 2006Hammad et al, 2008;Hughes et al, 2008;Jiang et al, 2007;Santucci et al, 2007), the concentrations of S1P ranged from 0.5 to 50 mM S1P and/or were conducted in the presence of serum, which has an S1P concentration of 0.4-1.1 mM (Yatomi et al, 1997). With the exception of the blood, in which S1P concentration ranges from 1 to 4 mM, the S1P content in all other tissue ranges from 0.5 to 75 pmol (mg tissue) 21 Edsall & Spiegel, 1999;Schwab et al, 2005).…”

“…Interestingly, treatment with exogenous S1P did not affect the growth of intracellular C. neoformans after 4 h (Fig. 1b), suggesting that S1P does not induce fungistatic or fungicidal actions of AMs against internalized C. neoformans as occurs in the Mycobacterium-macrophage interaction (Garg et al, 2004;Greco et al, 2010). …”

“…In contrast, the expression profile of the other S1P receptors (S1PRs) is cell-type-dependent, and the effects on the functions of immune cells have not been elucidated. Extracellular S1P has been shown to have numerous effects on macrophages, such as modulating receptor expression (Duong et al, 2004), inducing a proinflammatory state and increasing the killing of internalized Mycobacterium species (Garg et al, 2004;Sali et al, 2009). In addition to these antibacterial actions, exogenous S1P increases antigen processing and presentation in Mycobacterium tuberculosis-infected AMs (Santucci et al, 2007).…”