Abstract
Inflammatory (classical) monocytes residing in the bone marrow must enter the bloodstream in order to combat microbe infection. These monocytes express high levels of CCR2, a chemokine receptor whose activation is required for them to exit the bone marrow. How CCR2 is locally activated in the bone marrow and how their activation promotes monocyte egress is not understood. Here, we have used double transgenic lines that can visualize CCR2 activation in vivo and show that its chemokine ligand CCL2 is acutely released by stromal cells in the bone marrow, which make direct contact with CCR2-expressing monocytes. These monocytes also express CXCR4, whose activation immobilizes cells in the bone marrow, and are in contact with stromal cells expressing CXCL12, the CXCR4 ligand. During the inflammatory response, CCL2 is released and activates the CCR2 on neighboring monocytes. We demonstrate that acutely isolated bone marrow cells co-express CCR2 and CXCR4, and CCR2 activation desensitizes CXCR4. Inhibiting CXCR4 by a specific receptor antagonist in mice causes CCR2-expressing cells to exit the bone marrow in absence of inflammatory insults. Taken together, these results suggest a novel mechanism whereby the local activation of CCR2 on monocytes in the bone marrow attenuates an anchoring signalling provided by CXCR4 expressed by the same cell and mobilizes the bone marrow monocyte to the blood stream. Our results also provide a generalizable model that cross-desensitization of chemokine receptors fine-tunes cell mobility by integrating multiple chemokine signals.
Highlights
Innate immunity provides rapid protection from potentially harmful infection, before more specialized acquired immunity develops against specific antigens
Using CCL2::CCL2-mRFP;CCR2::CCR2-EGFP double transgenic mice, we examined where CCL2 and CCR2 proteins are expressed in the bone marrow under normal conditions (Fig 1A and inset)
Green and red arrows), reminiscent of immunological synapse described for T cells and B cells in lymph nodes [16]. These results indicate that CCL2 proteins are stored in these stromal cells that are juxtaposed to CCR2-expressing monocytes, but are not released
Summary
Innate immunity provides rapid protection from potentially harmful infection, before more specialized acquired immunity develops against specific antigens. Some chemokines show developmentally controlled or constitutive expression profiles, whereas others are upregulated under pathological conditions [2] The inducible chemokines, such as CCL2 (a.k.a. MCP-1), are responsible for coordinated leukocyte movements in response to microbial infection [3]. CCR2+ monocytes, which expressing a high level of the Ly6C surface antigen, are enriched in the bone marrow under normal circumstances, and targeted into inflamed tissues. For this reason, they are called Ly6C (high) or the classical monocytes. We reasoned that CCR2 activated during the inflammatory response might attenuate the force that normally retains the monocytes in the bone marrow, which is provided by CXCR4-mediated signaling
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