The polarization defect of Wiskott-Aldrich syndrome macrophages is linked to dislocalization of the Arp2/3 complex.
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally characterized by the clinical triad eczema, thrombocytopenia, and severe immunodeficieny, with recurrent bacterial and viral infections, indicating a profound immune cell defect. Such altered immune cells include monocytes, macrophages, and dendritic cells, which were reported to display disturbed cell polarization or chemotaxis. WAS is caused by mutations in the WAS protein (WASp), which is thought to organize the actin cytoskeleton through the Arp2/3 complex. Here we show that the Arp2/3 complex is an integral part of podosomes, actin-rich adhesion structures of macrophages, and that WAS macrophages fail to organize the Arp2/3 complex into podosomes. We also demonstrate that microinjection of a C-terminal acidic stretch of WASp into normal macrophages displaces Arp2/3 from podosomes and, in combination with chemoattractant stimulation of cells, induces a phenotype resembling the polarization-defective phenotype of stimulated WAS macrophages. These findings point to an important role of the Arp2/3 complex in polarization and migration of immune cells.
Linder
S
S
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten and Max von Pettenkofer-Institut für Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, München, Germany.
Higgs
H
H
Hüfner
K
K
Schwarz
K
K
Pannicke
U
U
Aepfelbacher
M
M
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016764:Cell Polarity / Q000276:immunology*; D003598:Cytoskeletal Proteins; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008845:Microinjections; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000276:immunology / Q000502:physiology; D011554:Pseudopodia / Q000737:chemistry / Q000502:physiology; D013194:Staining and Labeling; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein
C495926:ACTR2 protein, human; C495928:ACTR3 protein, human; D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; C495927:Actr2 protein, mouse; C495929:Actr3 protein, mouse; D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D011506:Proteins; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein