Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites

TLDR

Monocyte recruitment to inflammatory sites is governed by chemokines, yet the pathways controlling monocyte migration from bone marrow to blood and from blood to tissues remain poorly defined. Intravenous transfer of ex vivo‑labeled wild‑type or CCR2‑deficient bone marrow into wild‑type recipients showed that CCR2 is required for efficient recruitment of monocytes from blood to inflamed tissue. CCR2 deficiency reduces circulating monocytes but increases bone marrow monocytes, indicating CCR2 is essential for monocyte egress, while MCP‑3 and MCP‑1 are the key CCR2 agonists maintaining normal blood monocyte levels, underscoring the critical role of CCR2 and these chemokines in monocyte mobilization and leukocyte homeostasis.

Abstract

Monocyte recruitment to sites of inflammation is regulated by members of the chemokine family of chemotactic cytokines. However, the mechanisms that govern the migration of monocytes from bone marrow to blood and from blood to inflamed tissues are not well understood. Here we report that CC chemokine receptor 2 (CCR2) is highly expressed on a subpopulation of blood monocytes whose numbers are markedly decreased in CCR2(-/-) mice. In bone marrow, however, CCR2(-/-) mice had an increased number of monocytes, suggesting that CCR2 is critical for monocyte egress. Intravenous infusion of ex vivo-labeled WT or CCR2(-/-) bone marrow into WT recipient mice demonstrated that CCR2 is necessary for efficient monocyte recruitment from the blood to inflamed tissue. Analysis of mice lacking monocyte chemoattractant protein-1 (MCP-1), MCP-3, MCP-5, or MCP-2 plus MCP-5 revealed that MCP-3 and MCP-1 are the CCR2 agonists most critical for the maintenance of normal blood monocyte counts. These findings provide evidence that CCR2 and MCP-3/MCP-1 are critical for monocyte mobilization and suggest new roles for monocyte chemoattractants in leukocyte homeostasis.