Human neutrophils coordinate chemotaxis by differential activation of Rac1 and Rac2

J Immunol. 2009 Aug 15;183(4):2718-28. doi: 10.4049/jimmunol.0900849. Epub 2009 Jul 22.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemotaxis, Leukocyte / genetics
  • Chemotaxis, Leukocyte / immunology*
  • Dose-Response Relationship, Immunologic
  • Gene Products, tat / genetics
  • Gene Products, tat / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neuropeptides / antagonists & inhibitors
  • Neuropeptides / deficiency
  • Neuropeptides / metabolism*
  • Neutrophil Activation / genetics
  • Neutrophil Activation / immunology*
  • Oxidative Stress / immunology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Isoforms / physiology
  • RAC2 GTP-Binding Protein
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / physiology
  • rac GTP-Binding Proteins / antagonists & inhibitors
  • rac GTP-Binding Proteins / deficiency
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein

Substances

  • Gene Products, tat
  • Neuropeptides
  • Protein Isoforms
  • Rac1 protein, mouse
  • Recombinant Fusion Proteins
  • N-Formylmethionine Leucyl-Phenylalanine
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein