Distinct functions of CXCR4, CCR2, and CX3CR1 direct dendritic cell precursors from the bone marrow to the lung.
Precursors of dendritic cells (pre-DCs) arise in the bone marrow (BM), egress to the blood, and finally migrate to peripheral tissue, where they differentiate to conventional dendritic cells (cDCs). Upon their activation, antigen-bearing cDCs migrate from peripheral tissue to regional lymph nodes (LNs) in a manner dependent on the chemokine receptor, CCR7. To maintain immune homeostasis, these departing cDCs must be replenished by new cDCs that develop from pre-DCs, but the molecular signals that direct pre-DC trafficking from the BM to the blood and peripheral tissues remain poorly understood. In the present study, we found that pre-DCs express the chemokine receptors CXCR4, CCR2, and CX3CR1, and that each of these receptors has a distinct role in pre-DC trafficking. Flow cytometric analysis of pre-DCs lacking CXCR4 revealed that this receptor is required for the retention of pre-DCs in the BM. Analyses of mice lacking CCR2 or CX3CR1, or both, revealed that they promote pre-DC migration to the lung at steady state. CCR2, but not CX3CR1, was required for pre-DC migration to the inflamed lung. Thus, these multiple chemokine receptors cooperate in a step-wise fashion to coordinate the trafficking of pre-DCs from the BM to the circulation and peripheral tissues.
Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA nakanoh@niehs.nih.gov.
Hideki
H
Nakano
Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Miranda R
MR
Lyons-Cohen
Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Gregory S
GS
Whitehead
Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Keiko
K
Nakano
Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Donald N
DN
Cook
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
D000073883:CX3C Chemokine Receptor 1; C514936:CXCR4 protein, mouse; C515335:Ccr2 protein, mouse; C515371:Ccr7 protein, mouse; C471885:Cx3cr1 protein, mouse; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine
cell migration; chemokine; inflammation; monocytes; pre-DCs