Moreover, Ly6C+ monocytes are involved in atherosclerosis and can also differentiate into macrophages or myeloid suppressor cells . The role of Ly6C− monocytes remains more elusive. Ly6C− monocytes express high levels of CX3CR1, which allows them to patrol healthy tissues through long-range crawling on the surface of blood endothelium at the luminal side , in response to membrane-anchored endothelial CX3CL1 . This interaction is also required
for their survival . They express low levels of CCR2 and migrate less efficiently to inflamed tissues than inflammatory monocytes . They have been Erlotinib order proposed to be precursors of resident macrophage populations . Moreover, their human equivalent, the CD16+CD14dim monocytes respond to virus infection through TLR7 and TLR8 (where TLR is
Toll-like receptor) and produce TNF-α, IL-1β, and CC chemokine Ceritinib nmr Ligand 3 (CCL3) . A recent article also reported that Ly6C− monocytes were uniquely equipped with high levels of Fcγ receptors involved in antibody-dependent cell cytotoxicity such as FcγR1 and FcγR4 . Finally, they could also have a role in tissue repair and angiogenesis . Monocytes are produced in the BM from macrophage-DC precursor . Upon development, monocytes reach the blood circulation via BM sinusoids. Egress of Ly6C+ monocytes from BM has been shown to be dependent on CCR2. This egress is weak under steady-state conditions but increases massively upon inflammation induced by bacterial infection
. During infections, low concentrations of TLR ligands in the bloodstream drive CCR2-dependent emigration of monocytes from the BM. BM mesenchymal stem cells and CXC chemokine ligand 12 abundant reticular cells rapidly express CCL2 in response to TLR ligands or bacterial infection and induce monocyte egress into the blood . How Ly6C− monocytes reach the peripheral blood is however still unknown. Here, we report that Ly6C− monocytes expressed high levels of sphingosine-1 phosphate receptor 5 (S1PR5), previously involved in BM egress of natural killer (NK) cells . S1pr5−/− mice lack peripheral Ly6C− monocytes. Our data support a role for S1PR5 together with CCR2 in their egress from the BM. Modulation of extracellular S1P levels did not affect monocyte trafficking to the blood while it Teicoplanin reduced T-cell egress from lymphoid organs, showing that S1P receptors regulate the trafficking of monocytes and lymphocytes using different mechanisms. We measured using quantitative RT-PCR the expression of all S1PR in different lymphocyte and monocyte populations sorted by flow cytometry from the BM. S1PR5 showed the highest expression in monocyte subsets. S1PR5 was expressed 30 times higher in Ly6C− monocytes than in Ly6C+ monocytes (Fig. 1). A similar difference in S1PR5 expression between monocyte subsets has been measured using microarrays by the Immgen consortium (http://www.immgen.org/databrowser/index.html) .