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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4308-4313.
Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-09-3578.


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HEMATOPOIESIS

Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2

J. Pablo Abonia, K. Frank Austen, Barrett J. Rollins, Sunil K. Joshi, Richard A. Flavell, William A. Kuziel, Pandelakis A. Koni, and Michael F. Gurish

From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; the Molecular Immunology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT; and Autoimmune and Inflammatory Diseases, Protein Design Labs, Fremont, CA.

Homing of mast cell progenitors (MCps) to the mouse small intestine involves the interaction of {alpha}4{beta}7 integrin with mucosal addressin cellular adhesion molecule-1 (MAdCAM-1). We now demonstrate the dependence of this process on CXC chemokine receptor 2 (CXCR2) and vascular cell adhesion molecule-1 (VCAM-1) using null strains and mice sublethally irradiated and bone marrow (BM) reconstituted (SIBR) with wild-type or null BM or with wild-type BM followed by administration of blocking antibody. The intestinal MCp concentration in CXCR2-/- mice was reduced by 67%, but was unaltered in CC chemokine receptor 2-/- (CCR2-/-), CCR3-/-, or CCR5-/- mice. SIBR mice given CXCR2-/- BM had an intestinal MCp concentration that was 76% less than that in BALB/c BM reconstituted mice. Antibody blockade of VCAM-1 or of CXCR2 in SIBR mice reduced intestinal MCp reconstitution, and mice lacking endothelial VCAM-1 also had a marked reduction relative to wild-type mice. Finally, the half-life of intestinal MCps in wild-type mice was less than one week on the basis of a more than 50% reduction by administration of anti-{alpha}4{beta}7 integrin or anti-CXCR2. Thus, the establishment and maintenance of MCps in the small intestine is a dynamic process that requires expression of the {alpha}4{beta}7 integrin and the {alpha}-chemokine receptor CXCR2.


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