Chemotaxis of macrophages is abolished in the Wiskott‐Aldrich syndrome

Zicha, Daniel; Allen, William E.; Brickell, Paul M.; Kinnon, Christine; Dunn, Graham; Jones, Gareth E.; Thrasher, Adrian J.

doi:10.1046/j.1365-2141.1998.00767.x

Cited by 226 publications

(187 citation statements)

References 44 publications

(37 reference statements)

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“…2 and 3). Reduced podosome formation causes the failure of chemotaxis in WAS macrophages, contributing to recurrent infections in WAS patients (33,51).…”

Section: Discussionmentioning

confidence: 99%

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Tsuboi

2007

The Journal of Immunology

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Chemotactic migration of macrophages is critical for the recruitment of leukocytes to inflamed tissues. Macrophages use a specialized adhesive structure called a podosome to migrate. Podosome formation requires the Wiskott-Aldrich syndrome protein (WASP), which is a product of the gene defective in an X-linked inherited immunodeficiency disorder, the Wiskott-Aldrich syndrome. Macrophages from WASP-deficient Wiskott-Aldrich syndrome patients lack podosomes, resulting in defective chemotactic migration. However, the molecular basis for podosome formation is not fully understood. I have shown that the WASP interacting protein (WIP), a binding partner of WASP, plays an important role in podosome formation in macrophages. I showed that WASP bound WIP to form a complex at podosomes and that the knockdown of WIP impairs podosome formation. When WASP binding to WIP was blocked, podosome formation was also impaired. When WASP expression was reduced by small interfering RNA transfection, the amount of the complex of WASP with WIP decreased, resulting in reduced podosome formation. Podosomes were restored by reconstitution of the WASP-WIP complex in WASP knockdown cells. These results indicate that the WASP-WIP complex is required for podosome formation in macrophages. When podosome formation was reduced by blocking WASP binding to WIP, transendothelial migration of macrophages, the most crucial process in macrophage trafficking, was impaired. These results suggest that a complex of WASP with WIP plays a critical role in podosome formation, thereby mediating efficient transendothelial migration of macrophages.

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“…2 and 3). Reduced podosome formation causes the failure of chemotaxis in WAS macrophages, contributing to recurrent infections in WAS patients (33,51).…”

Section: Discussionmentioning

confidence: 99%

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Tsuboi

2007

The Journal of Immunology

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“…It is likely that mutant DCs are defective for chemotaxis (the directional response to stimuli) as has been observed in macrophages. 27,29 This reflects defective polarization and formation of filopodia, which are necessary for a normal chemotactic response as demonstrated by inhibition of Cdc42 in a Bac1 macrophage cell line. 37 However, the quality of migration of WASp-null DCs is also highly disturbed, both in terms of development of a dominant leading edge and retraction of the tail.…”

Section: Discussionmentioning

confidence: 99%

“…12 The pathophysiology of WAS relates to defective polymerization of [20][21][22][23][24][25][26] However, defects of migration identified in myeloid and T cells in vitro, and stem cells in vivo, [27][28][29][30][31] all support the hypothesis that many of the immunologic consequences of WASp deficiency arise from abnormal cell homing and spatial localization.…”

Section: Introductionmentioning

confidence: 99%

Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein

Noronha

2005

Blood

109

102

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IntroductionDendritic cells (DCs) are highly motile bone marrow-derived antigen-presenting cells (APCs). They have specialized migratory and homing properties that allow them both to initiate primary immune responses and to induce tolerance. 1,2 In lymphoid organs they are present as interdigitating cells in the white pulp of the spleen and in the paracortex of lymph nodes (LNs) where they are able to capture incoming foreign antigen from blood or lymph, respectively. In nonlymphoid tissues DCs act as sentinels of injury and patrol for the presence of foreign antigens and pathogens. Upon capture they migrate to draining secondary lymphoid tissue during which time they mature and develop the capacity to stimulate antigen specific T cells.The migration and spatial localization of DCs are controlled by numerous extrinsic factors, including chemokine family members to which they are responsive through maturation and localizationdependent mechanisms. [3][4][5][6][7] The physical motility of cells and anchorage in specific tissues is, however, ultimately dependent on the regulated dynamics of the actin cytoskeleton, which determines the response of cells to chemokine gradients and enables purposeful movement through the sequential process of leading-edge protrusion, attachment, and tail retraction. 8 The molecular control of this highly coordinated activity is orchestrated by Rho family guanosine triphosphatases (GTPases), the best characterized of which are Cdc42, Rac1/2, and RhoA, and their downstream effectors. 9 In hematopoietic cells, a key effector for Cdc42 is the Wiskott-Aldrich syndrome protein (WASp). WASp is a 502-amino acid member of a conserved family of proteins that participate in the organization of actin polymerization primarily through activation of the actin-related protein (Arp2/Arp3) complex. [10][11][12] Interference in these signaling pathways results in multiple cytoskeletal defects in DCs, including the failure to form normal membrane projections and specialized structures known as podosomes, which form behind the leading edge of motile cells. [13][14][15][16] Podosomes concentrate ␤2 integrins around an actin core and, although their function has not been clearly identified, are responsible for tight adhesion of cells to intercellular adhesion molecule-1 (ICAM-1) and possibly junctional adhesion molecule-A (JAM-A). [17][18][19] Furthermore, they are highly dynamic with a turnover of minutes, providing a migrating cell with a mechanism for rapid attachment and detachment, and with localized anchorage points that could facilitate traverse of endothelial barriers in particular.Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, eczema, and autoimmunity. 12 The pathophysiology of WAS relates to defective polymerization of [20][21][22][23][24][25][26] However, defects of migration identified in myeloid and T cells in vitro, and stem cells in vivo, [27][28][29][30][31] all support the hypothesis that many of the immunologic consequences of WASp deficiency ar...

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“…By binding to Cdc42, to phosphatidyl inositol (4,5) bisphosphate (PI(4,5)P2) and to the actin nucleating Arp2/3 complex, WASP nucleates actin polymerization (Rohatgi et al, 1999). In macrophages from WAS patients in which WASp is truncated and not functional, podosome formation and macrophage chemotaxis are dramatically impaired (Zicha et al, 1998;Linder et al, 1999). Critical function of WASp is supported by analysis of dendritic cells or osteoclasts coming from WASp (Burns et al, 2001;Calle et al, 2004) and WIP (WASp interacting protein) null mice (Chou et al, 2006;Chabadel et al, 2007).…”

Section: Wasp a Cdc42 Effector And A Key Organizer Of Podosomesmentioning

confidence: 99%

Rho GTPases in osteoclasts: Orchestrators of podosome arrangement

Ory

Brazier

Pawlak

et al. 2008

European Journal of Cell Biology

130

101

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Cells from the myeloid lineage, namely macrophages, dendritic cells and osteoclasts develop podosomes instead of stress fibers and focal adhesions to adhere and migrate.Podosomes share many components with focal adhesions but differ in their molecular organization, with a dense core of polymerized actin surrounded by scaffolding proteins, kinases and integrins. Podosomes are found either isolated both in macrophages and dendritic cells or arranged into superstructures in osteoclasts. When osteoclasts resorb bone, they form an F-actin rich sealing zone, which is a dense array of connected podosomes that firmly anchors osteoclasts to bone. It delineates a compartment in which protons and proteases are secreted to dissolve and degrade the mineralized matrix. Since Rho GTPases have been shown to control F-actin stress fibers and focal adhesions in mesenchymal cells, the question of whether they could also control podosome formation and arrangement in cells from the myeloid lineage, and particularly in osteoclasts, rapidly emerged. This article considers recent advances made in our understanding of podosome arrangements in osteoclasts and how Rho GTPases may control it.

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Chemotaxis of macrophages is abolished in the Wiskott‐Aldrich syndrome

Cited by 226 publications

References 44 publications

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein

Rho GTPases in osteoclasts: Orchestrators of podosome arrangement

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