CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses.
It is well established that Ly6Chimonocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chimonocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chimonocytes consist of two distinct subpopulations (CXCR4hiand CXCR4losubpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hisubset proliferates and is immobilized in the BM for the replenishment of functionally mature CXCR4lomonocytes. We propose that the CXCR4hisubset represents a transitional premonocyte population, and that this sequential step of maturation from cMoPs serves to maintain a stable pool of BM monocytes. Additionally, reduced CXCR4 expression on monocytes, upon their exit into the circulation, does not reflect its diminished role in monocyte biology. Specifically, CXCR4 regulates monocyte peripheral cellular activities by governing their circadian oscillations and pulmonary margination, which contributes toward lung injury and sepsis mortality. Together, our study demonstrates the multifaceted role of CXCR4 in defining BM monocyte heterogeneity and in regulating their function in peripheral tissues.
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore Ng_Lai_Guan@immunol.a-star.edu.sg Chong_Shu_Zhen@immunol.a-star.edu.sg.
Shu Zhen
SZ
Chong
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.|School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
Maximilien
M
Evrard
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Sapna
S
Devi
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Jinmiao
J
Chen
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Jyue Yuan
JY
Lim
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Peter
P
See
Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Biopolis, 138673 Singapore.
Yiru
Y
Zhang
Area of Cell and Developmental Biology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
José M
JM
Adrover
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Bernett
B
Lee
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Leonard
L
Tan
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Jackson L Y
JL
Li
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Ka Hang
KH
Liong
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Cindy
C
Phua
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Akhila
A
Balachander
Institute of Medical Biology (IMB)-Institute of Molecular and Cell Biology (IMCB) Electron Microscopy Suite, A*STAR (Agency for Science, Technology and Research), Biopolis, 138671 Singapore.
Adrian
A
Boey
Institute of Medical Biology (IMB)-Institute of Molecular and Cell Biology (IMCB) Electron Microscopy Suite, A*STAR (Agency for Science, Technology and Research), Biopolis, 138671 Singapore.
David
D
Liebl
School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
Suet Mien
SM
Tan
Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore.|Department of Reproductive Medicine, KK Women's and Children's Hospital, 229899 Singapore.|Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 169857 Singapore.
Jerry K Y
JK
Chan
INSERM UMR-S996, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Université Paris-Sud, 92140 Clamart, France.
Karl
K
Balabanian
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
John E
JE
Harris
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich 80336, Germany.
Mariaelvy
M
Bianchini
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich 80336, Germany.
Christian
C
Weber
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich 80336, Germany.
Johan
J
Duchene
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Josephine
J
Lum
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Michael
M
Poidinger
Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Biopolis, 138673 Singapore.
Qingfeng
Q
Chen
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Laurent
L
Rénia
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Cheng-I
CI
Wang
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Anis
A
Larbi
Division of Immunobiology, Washington University, St. Louis, MO 63110.
Gwendalyn J
GJ
Randolph
Centenary Institute for Cancer Medicine and Cell Biology, Newton, New South Wales 2042, Australia.
Wolfgang
W
Weninger
Department of Medicine and Pathology, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143.
Mark R
MR
Looney
Department of Medicine and Pathology, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143.
Matthew F
MF
Krummel
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Subhra K
SK
Biswas
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore.
Florent
F
Ginhoux
Area of Cell and Developmental Biology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.|Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich 80336, Germany.
Andrés
A
Hidalgo
INSERM UMR-S996, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Université Paris-Sud, 92140 Clamart, France.
Françoise
F
Bachelerie
Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore Ng_Lai_Guan@immunol.a-star.edu.sg Chong_Shu_Zhen@immunol.a-star.edu.sg.|School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
Lai Guan
LG
Ng
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D020869:Gene Expression Profiling; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*
D000950:Antigens, Ly; D004731:Endotoxins; C494192:Ly-6C antigen, mouse; D019718:Receptors, CXCR4