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

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

The Journal of experimental medicine (2013-10-02)
Sapna Devi, Yilin Wang, Weng Keong Chew, Ronald Lima, Noelia A-González, Citra N Z Mattar, Shu Zhen Chong, Andreas Schlitzer, Nadja Bakocevic, Samantha Chew, Jo L Keeble, Chi Ching Goh, Jackson L Y Li, Maximilien Evrard, Benoit Malleret, Anis Larbi, Laurent Renia, Muzlifah Haniffa, Suet Mien Tan, Jerry K Y Chan, Karl Balabanian, Takashi Nagasawa, Françoise Bachelerie, Andrés Hidalgo, Florent Ginhoux, Paul Kubes, Lai Guan Ng
RESUMEN

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.

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AMD3100 octahydrochloride hydrate, ≥97% (NMR), solid

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