The small Rho GTPase Cdc42 regulates neutrophil polarity via CD11b integrin signaling.
Neutrophil migration to sites of infection is the first line of cellular defense. A key event of migration is the maintenance of a polarized morphology, which is characterized by a single leading edge of filamentous actin and a contractile uropod devoid of filamentous actin protrusions. Using a mouse model of high Cdc42 activity, we previously demonstrated the importance of Cdc42 activity in neutrophil migration. However, the specific functions of Cdc42 in this process remain to be understood. Using neutrophils genetically deficient in Cdc42, we show that Cdc42 regulates directed migration by maintaining neutrophil polarity. Although it is known to be activated at the front, Cdc42 suppresses protrusions at the uropod. Interestingly, Cdc42 makes use of the integrin CD11b during this process. Cdc42 determines the redistribution of CD11b at the uropod. In turn, using CD11b-null cells and CD11b crosslinking experiments, we show that CD11b modulates myosin light chain phosphorylation to suppress lateral protrusions. Our results uncover a new mechanism in which Cdc42 regulates the uropod through CD11b signaling to maintain polarity in migrating neutrophils. It also reveals new functions for CD11b in neutrophil polarity.
Szczur
Kathleen
K
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Zheng
Yi
Y
Filippi
Marie-Dominique
MD
D000818:Animals; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D005455:Fluorescent Antibody Technique; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism*
D039481:CD11b Antigen; D020764:cdc42 GTP-Binding Protein