Human neutrophils coordinate chemotaxis by differential activation of Rac1 and Rac2.
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.
Zhang
Hui
H
Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037-1092, USA.
Sun
Chunxiang
C
Glogauer
Michael
M
Bokoch
Gary M
GM
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D015696:Gene Products, tat / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
D015696:Gene Products, tat; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009479:Neuropeptides; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse