Bone marrow mesenchymal stem cells calibrate the innate immune tone by inducing monocyte emigration in response to circulating TLR-ligands (162.1)

Abstract

Abstract Inflammatory (Ly6Chi CCR2+) monocytes provide defense against infections but also contribute to autoimmune diseases and atherosclerosis. Monocytes originate from the bone marrow and their entry into the bloodstream requires stimulation of CCR2 chemokine receptors by MCP1. How monocyte emigration from bone marrow is triggered by infections in anatomically remote sites remains unclear. We demonstrate that low concentrations of TLR ligands in the bloodstream drive CCR2-dependent emigration of monocytes from bone marrow. Bone marrow mesenchymal stem cells (MSCs) rapidly express MCP1 in response to circulating TLR ligands or systemic bacterial infection and induce inflammatory monocyte trafficking into the bloodstream. Targeted deletion of MCP1 from MSCs impaired monocyte emigration from bone marrow upon LPS stimulation and increased susceptibility to Listeria monocytogenes infection. Our findings suggest that bone marrow MSCs respond to circulating microbial molecules and regulate bloodstream monocyte frequencies by secreting MCP1 in proximity to bone marrow vascular sinuses.