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Blood, 1 May 2007, Vol. 109, No. 9, pp. 4028-4037.
Prepublished online as a Blood First Edition Paper on January 3, 2007; DOI 10.1182/blood-2006-10-055319.
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PHAGOCYTES
Tumor suppressor PTEN is a physiologic suppressor of chemoattractant-mediated neutrophil functions
Kulandayan K. Subramanian1,2,
Yonghui Jia1,2,
Daocheng Zhu1,2,
Benjamin T. Simms3,
Hakryul Jo3,
Hidenori Hattori1,2,
Jian You1,2,
Joseph P. Mizgerd3, and
Hongbo R. Luo1,2
1 epartment of Pathology, Harvard Medical School, Boston, MA;
2 Department of Lab Medicine and Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA;
3 Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA
The recruitment and activation of neutrophils at infected tissues is essential for host defense against invading microorganisms. However, excessive neutrophil recruitment or activation can also damage the surrounding tissues and cause unwanted inflammation. Hence, the responsiveness of neutrophils needs to be tightly regulated. In this study, we have investigated the functional role of tumor suppressor PTEN in neutrophils by using a mouse line in which PTEN is disrupted only in myeloid-derived cells. Chemoattractant-stimulated PTEN–/– neutrophils displayed significantly higher Akt phosphorylation and actin polymerization. A larger fraction of these neutrophils displayed membrane ruffles in response to chemoattractant stimulation. In addition, chemoattractant-induced transwell migration and superoxide production were also augmented. Single-cell chemotaxis assays showed that PTEN–/– neutrophils have a small (yet statistically significant) defect in directionality. However, these neutrophils also showed an increase in cell speed. As a result, overall chemotaxis, which depends on speed and directionality, was not affected. Consistent with the increased responsivenessof PTEN–/– neutrophils, the in vivo recruitment of these cells to the inflamed peritoneal cavity was significantly enhanced. Thus, as a physiologic-negative regulator, PTEN should be a promising therapeutic target for modulating neutrophil functions in various infectious and inflammatory diseases.
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