Dual Roles for Rac2 in Neutrophil Motility and Active Retention in Zebrafish Hematopoietic Tissue

• Published in: Developmental cell 2011-10, Vol.21 (4), p.735-745
• Main Authors: Deng, Qing, Yoo, Sa Kan, Cavnar, Peter J., Green, Julie M., Huttenlocher, Anna
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Agammaglobulinemia - complications; Animals; Animals, Genetically Modified; Bacteria; Bacterial Infections - complications; Biological and medical sciences; Blotting, Western; Bone Marrow - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell Movement - physiology; Cell physiology; Danio rerio; Fluorescent Antibody Technique; Freshwater; Fundamental and applied biological sciences. Psychology; Hematopoietic System - physiology; HL-60 Cells; Humans; Immunologic Deficiency Syndromes - complications; Larva - metabolism; Larva - microbiology; Molecular and cellular biology; Mutation - genetics; Neutrophils - cytology; Neutrophils - metabolism; rac GTP-Binding Proteins - physiology; RAC2 GTP-Binding Protein; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Warts - complications; Zebrafish - genetics; Zebrafish - growth & development; Zebrafish - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.07.013

Neutrophil homeostasis is essential for host defense. Here we identify dual roles for Rac2 during neutrophil homeostasis using a zebrafish model of primary immune deficiency induced by the human inhibitory Rac2D57N mutation in neutrophils. Noninvasive live imaging of Rac2 morphants or Rac2D57N zebrafish larvae demonstrates an essential role for Rac2 in regulating 3D motility and the polarization of F-actin dynamics and PI(3)K signaling in vivo. Tracking of photolabeled Rac2-deficient neutrophils from hematopoietic tissue also shows increased mobilization into the circulation, indicating that neutrophil mobilization does not require traditionally defined cell motility. Moreover, excessive neutrophil retention in hematopoietic tissue resulting from a constitutively active CXCR4 mutation in zebrafish warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is partially rescued by the inhibitory Rac2 mutation. These findings reveal that Rac2 signaling is necessary for both neutrophil 3D motility and CXCR4-mediated neutrophil retention in hematopoietic tissue, thereby limiting neutrophil mobilization, a critical first step in the innate immune response. [Display omitted] ► Human Rac2D57N mutation in neutrophils induces immune deficiency in zebrafish ► In vivo imaging shows that Rac2 is necessary for neutrophil polarity and migration ► Rac2 mediates neutrophil retention in hematopoietic tissue and limits mobilization ► Rac2 is necessary for CXCR4-mediated neutrophil retention in hematopoietic tissue