SevereListeria monocytogenesInfection Induces Development of Monocytes with Distinct Phenotypic and Functional Features

Abstract

Monocytes perform diverse roles during infection with the facultative intracellular bacterium Listeria monocytogenes. They are essential as bactericidal cells in host defense but can also become Trojan horses transporting bacteria into the brain. To explain these contrasting roles, we characterized bone marrow (BM) monocytes in steady state and generated during lethal and sublethal L. monocytogenes infection. Ly-6ChighCD11b+ BM monocytes expressed high amounts of M-CSFR/CD115 in steady state and 72 h following sublethal infection. However, infection with increasing numbers of bacteria resulted in progressive loss of CD115 and strongly decreased CD115-encoding c-fms mRNA expression. Conversely, analysis of regulatory molecules showed de novo expression of the nonsignaling IL-1RII, CD121b, under the same conditions. Ly-6ChighCD11b+ monocytes in circulation also acquired a CD115neg/lowCD121bhigh phenotype during lethal infection. These BM monocytes showed upregulation of suppressor of cytokine signaling 1 and 3 and IL-1R–associated kinase-M to a greater extent and/or earlier compared with cells from sublethal infection and showed decreased LPS-induced IL-6 production despite similar levels of surface TLR4 expression. BM monocytes from uninfected or sublethally infected mice bound and internalized very few L. monocytogenes in vitro. However, both functions were significantly increased in monocytes developing during lethal infection. Nonetheless, these cells did not produce reactive oxygen intermediates, suggesting an inability to kill L. monocytogenes. Together, these data show that systemic infections with lethal and sublethal amounts of bacteria differentially shape developing BM monocytes. This results in distinct phenotypic and functional properties consistent with being Trojan horses rather than bactericidal effector cells.

MicroRNA-Mediated Down-Regulation of M-CSF Receptor Contributes to Maturation of Mouse Monocyte-Derived Dendritic Cells

“…TMI-1 and -2 treatment of GM-DC by itself already caused a decrease in M-CSFR expression, which was not caused by decreased cell viability (not shown). The efficacy of the TACE inhibitors under these conditions is indicated by the inhibition of spontaneous and LPS-induced decrease of membrane-bound M-CSFR on BM monocytes [compare left panels in Figure 3C to approximately 80% M-CSFR-expressing BM monocytes upon isolation (39)] (Figure 3C). Collectively, these data suggest that TACE-mediated shedding does not play a major role in reducing M-CSFR expression on maturing GM-DC.…”

“…Additionally, various pro-inflammatory stimuli cause enzymatic cleavage of the M-CSFR ectodomain by TNFα-converting enzyme (TACE)-mediated shedding in vitro (38, 53, 54). However, in vivo down-regulation of surface M-CSFR expression under inflammatory conditions can also be TACE-independent, since TACE was not responsible for absence of M-CSFR expression from monocytes generated during severe L. monocytogenes infection (39). Our current experiments indicated that TACE also did not play a major role in M-CSFR down-regulation in final GM-DC maturation in vitro .…”

Role of Suppressor of Cytokine Signaling-1 In Murine Atherosclerosis

“…[24] In addition, increased SOCS-1 expression in monocytes infected with hepatitis C aggravates disease activity by modulating IL-12 secretion while in Ly-6C hi monocytes isolated from bone-marrow of C57BL/6 mice infected with Listeria monocytogenesis early SOCS-1 expression is associated with host outcome. [25], [26].…”

Monocytes Are the Predominant Cell Type Associated with Listeria monocytogenes in the Gut, but They Do Not Serve as an Intracellular Growth Niche

“…More recently, Drevets et al showed that most of the L. monocytogenes -associated cells in the blood after i.v. infection of mice were Ly6C hi monocytes (21), and that only cells with an altered phenotype that appeared late (72 h) after lethal injection could efficiently internalize the bacteria (22). Monocytes are produced in the bone marrow, and rapid egress into the bloodstream during inflammation is dependent on expression of the chemokine receptor CCR2 (23).…”