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00925njm 22002777a 4500 dc Chong, Shu Zhen author Evrard, Maximilien author Devi, Sapna author Chen, Jinmiao author Lim, Jyue Yuan author See, Peter author Zhang, Yiru author Adrover, Jose M author Lee, Bernett author Tan, Leonard author Li, Jackson L. Y. author Liong, Ka Hang author Phua, Cindy author Balachander, Akhila author Boey, Adrian author Liebl, David author Tan, Suet Mien author Chan, Jerry K. Y. author Balabanian, Karl author Harris, John E. author Bianchini, Mariaelvy author Weber, Christian author Duchene, Johan author Lum, Josephine author Poidinger, Michael author Chen, Qingfeng author Renia, Laurent author Wang, Cheng-I author Larbi, Anis author Randolph, Gwendalyn J. author Weninger, Wolfgang author Looney, Mark R. author Krummel, Matthew F. author Biswas, Subhra K. author Ginhoux, Florent author Hidalgo, Andres author Bachelerie, Françoise author Ng, Lai Guan author 2016 It is well established that Ly6C(hi) monocytes 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 Ly6C(hi) monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6C(hi) monocytes consist of two distinct subpopulations (CXCR4(hi) and CXCR4(lo) subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4(hi) subset proliferates and is immobilized in the BM for the replenishment of functionally mature CXCR4(lo) monocytes. We propose that the CXCR4(hi) subset 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. J Exp Med. 2016; 213(11):2293-2314 10.1084/jem.20160800 1540-9538 0022-1007 Journal of Experimental Medicine 27811056 http://hdl.handle.net/20.500.12105/5181 WHIM-SYNDROME LUNG INJURY CHEMOKINE RECEPTOR PROGENITOR CELLS EXTRAMEDULLARY HEMATOPOIESIS INFLAMMATORY MONOCYTES MYOCARDIAL-INFARCTION DENDRITIC CELLS NEUTROPHIL MICE CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses