Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow

Author:

Devi Sapna1,Wang Yilin1,Chew Weng Keong1,Lima Ronald2,A-González Noelia3,Mattar Citra N.Z.4,Chong Shu Zhen1,Schlitzer Andreas1,Bakocevic Nadja1,Chew Samantha1,Keeble Jo L.1,Goh Chi Ching1,Li Jackson L.Y.1,Evrard Maximilien1,Malleret Benoit1,Larbi Anis1,Renia Laurent1,Haniffa Muzlifah15,Tan Suet Mien6,Chan Jerry K.Y.478,Balabanian Karl9,Nagasawa Takashi1011,Bachelerie Françoise9,Hidalgo Andrés3,Ginhoux Florent1,Kubes Paul2,Ng Lai Guan1

Affiliation:

1. Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore

2. Calvin, Phoebe, and Joan Snyder Institute for Infection, Immunity, and Inflammation, University of Calgary, Alberta T2N 1N4, Canada

3. Department of Epidemiology, Atherothrombosis and Imaging, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain

4. Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore

5. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK

6. School of Biological Sciences, Nanyang Technological University, 637551 Singapore

7. Department of Reproductive Medicine, KK Women’s and Children’s Hospital, 229899 Singapore

8. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 169857 Singapore

9. Inserm Unite Mixte de Recherche (UMR) S996, Universiteì Paris-Sud, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, 92140 Clamart, France

10. Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan

11. Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0076, Japan

Abstract

Blood neutrophil homeostasis is essential for successful host defense against invading pathogens. Circulating neutrophil counts are positively regulated by CXCR2 signaling and negatively regulated by the CXCR4–CXCL12 axis. In particular, G-CSF, a known CXCR2 signaler, and plerixafor, a CXCR4 antagonist, have both been shown to correct neutropenia in human patients. G-CSF directly induces neutrophil mobilization from the bone marrow (BM) into the blood, but the mechanisms underlying plerixafor-induced neutrophilia remain poorly defined. Using a combination of intravital multiphoton microscopy, genetically modified mice and novel in vivo homing assays, we demonstrate that G-CSF and plerixafor work through distinct mechanisms. In contrast to G-CSF, CXCR4 inhibition via plerixafor does not result in neutrophil mobilization from the BM. Instead, plerixafor augments the frequency of circulating neutrophils through their release from the marginated pool present in the lung, while simultaneously preventing neutrophil return to the BM. Our study demonstrates for the first time that drastic changes in blood neutrophils can originate from alternative reservoirs other than the BM, while implicating a role for CXCR4–CXCL12 interactions in regulating lung neutrophil margination. Collectively, our data provides valuable insights into the fundamental regulation of neutrophil homeostasis, which may lead to the development of improved treatment regimens for neutropenic patients.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3