Role of Rho family GTPases in CCR1- and CCR5-induced actin reorganization in macrophages.
The beta-chemokines, MIP-1alpha/CCL3, MIP-1beta/CCL4, and RANTES/CCL5, play a critical role in the selective accumulation and activation of macrophages in inflamed tissues. Herein, we demonstrate that the binding of each of these beta-chemokines to their cognate receptors, CCR1 and CCR5, in either macrophages or in CCR1- or CCR5-transfected CHO cells, induced actin reorganization and the formation of lamellipodia that are characteristic of the activation of the Rho family GTPase, Rac. A dominant negative mutant of Rac, but not dominant negative mutants of RhoA or Cdc42, blocked MIP-1alpha-induced lamellipodia formation. Moreover, this MIP-1alpha-induced Rac activation and consequent lamellipodia formation is Gi- and phosphoinositide-3 kinase (PI3K)-mediated. Thus, Rac activation is critical for both CCR1- and CCR5-triggered signaling cascades mediating beta-chemokine-induced reorganization of the actin cytoskeleton, a process essential for effective recruitment and activation of macrophages in inflammation.
Di Marzio
Paola
P
Center for Immunology and Inflammation, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA.
Dai
Wei Wei
WW
Franchin
Giovanni
G
Chan
Amanda Y
AY
Symons
Marc
M
Sherry
Barbara
B
D000199:Actins / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003001:Cloning, Molecular; D006224:Cricetinae; D017931:DNA Primers; D020558:GTP Phosphohydrolases / Q000502:physiology*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*
D000199:Actins; C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017931:DNA Primers; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D020558:GTP Phosphohydrolases