Published online before print June 26, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.071059

Accepted for publication April 29, 2008.

Article

The Role of Rac2 in Regulating Neutrophil Production in the Bone Marrow and Circulating Neutrophil Counts

John C. Gomez^*, Jindrich Soltys^*, Keiichi Okano^*, Mary C. Dinauer, and Claire M. Doerschuk^*@

From the Department of Pediatrics,* Division of Integrative Biology, Rainbow Babies and Children's Hospital and Case Western Reserve University, and the Department of Pathology, Case Western Reserve University, Cleveland, Ohio; and the Cancer Research Institute, Indiana University School of Medicine, Indianapolis, Indiana

^@ To whom correspondence should be addressed. E-mail: cmd{at}med.unc.edu.

	Abstract

Circulating neutrophils are persistently higher in mice deficient in the small GTPase Rac2 than in wild-type (WT) mice. Therefore, we examined the mechanisms through which the small GTPase Rac2 regulates neutrophil production and release. Lethally irradiated WT mice reconstituted with a 50:50 mixture of WT and Rac2^-/- fetal liver cells were protected from neutrophilia, suggesting that neutrophilia is primarily because of extrinsic defects that can be corrected by WT leukocytes. However, the differential counts and numbers of leukocyte subtypes differed between Rac2^-/- and WT cells, suggesting that Rac2 modulates leukocyte lineage distribution. Kinetic studies suggest Rac2 modulates the release of neutrophils into the circulation and does not prolong their circulating half life. The percentage of bone marrow cells that expressed the neutrophil marker Gr-1 in lethally irradiated WT or Rac2^-/- recipients of Rac2^-/- stem cells was greater than in recipients of WT stem cells; however, circulating neutrophil counts were higher only in Rac2^-/- recipients of Rac2^-/- stem cells. Rac2 mRNA was expressed in the bone marrow of WT recipients of Rac2^-/- stem cells and in human mesenchymal stem cells. The data presented here suggest that Rac2 in hematopoietic cells regulates leukocyte lineage distribution and Rac2 in nonhematopoietic cells might contribute to regulating circulating neutrophil counts.