HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900849v1 183/4/2718    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zhang, H. Articles by Bokoch, G. M. PubMed PubMed Citation Articles by Zhang, H. Articles by Bokoch, G. M.

Human Neutrophils Coordinate Chemotaxis by Differential Activation of Rac1 and Rac2¹

Hui Zhang^*, Chunxiang Sun, Michael Glogauer and Gary M. Bokoch^2,*

^* Department of Immunology and Microbial Science and Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037; and Canadian Institutes for Health Research Group in Matrix Dynamics and Dental Research Institute, University of Toronto, Faculty of Dentistry, Toronto, Ontario, Canada

Rac1 and Rac2, members of the small Rho GTPase family, play essential roles in coordinating directional migration and superoxide production during neutrophil responses to chemoattractants. Although earlier studies in Rac1 and Rac2 knockout mice have demonstrated unique roles for each Rac isoform in chemotaxis and NADPH oxidase activation, it is still unclear how human neutrophils use Rac1 and Rac2 to achieve their immunological responses to foreign agent stimulation. In the current study, we used TAT dominant-negative Rac1-T17N and Rac2-T17N fusion proteins to acutely alter the activity of Rac1 and Rac2 individually in human neutrophils. We demonstrate distinct activation kinetics and different roles for Rac1 and Rac2 in response to low vs high concentrations of fMLP. These observations were verified using neutrophils from mice in which Rac1 or Rac2 was genetically absent. Based on these results, we propose a model to explain how human neutrophils kill invading microbes while limiting oxidative damage to the adjacent surrounding healthy tissue through the differential activation of Rac1 and Rac2 in response to different concentrations of chemoattractant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant GM39434 from the National Institutes of Health (to G.M.B.) and a Canadian Institutes of Health Research operating grant (to M.G.).

² Address correspondence and reprint requests to Dr. Gary M. Bokoch, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037-1092.

³ Abbreviations used in this paper: ROS, reactive oxygen species; DAPI, 4',6-diamidino-2-phenylindole; DIAS, Dynamic Image Analysis System; DIC, differential interference contrast; GEF, guanine nucleotide exchange factor.

⁴ The online version of this article contains supplemental material.