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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents

ID: 744130.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
HS1 deficiency impairs neutrophil recruitment in vivo and activation of the small GTPases Rac1 and Rap1
Authors:Latasiewicz, J.; Artz, A.; Jing, D.; Blanco, M. P.; Currie, S. M.; Avila, M. V.; Schnoor, M.; Vestweber, D.
Date of Publication (YYYY-MM-DD):2017-05
Title of Journal:J Leukoc Biol
Issue / Number:5
Start Page:1133
End Page:1142
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Neutrophil extravasation is a critical step of the innate immune system's response to inflammation. This multistep process is tightly regulated by adhesion and signaling molecules in the endothelium and neutrophils. Activation of the beta2 integrin LFA-1 is critical for adhesion of leukocytes to postcapillary venules. This step requires coordinated activation of signaling pathways in chemokine-stimulated neutrophils, including GTPase activation and cytoskeletal remodeling, leading to conformational changes in LFA-1. Hematopoietic cell-specific lyn substrate 1 (HS1) is a cortactin-related and leukocyte-specific actin-binding protein (ABP) that regulates several processes in various immune cells. It has been shown in vitro that HS1 is important for neutrophil chemotaxis and transendothelial migration of NK cells, but its role in neutrophil extravasation in vivo has not been investigated yet. Intravital microscopy of CXCL1-stimulated cremaster venules revealed an increased rolling velocity and reduced neutrophil adhesion and transmigration in HS1 knockout (KO) mice. CXCL1-induced rapid neutrophil arrest in vivo and adhesion under flow conditions in vitro were also reduced significantly. Whereas random motility of neutrophils was unaffected, chemotaxis toward a CXCL1 gradient was reduced in the absence of HS1. Further analysis of the underlying mechanisms demonstrated that HS1 controls CXCL1-induced activation of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and Ras-related protein 1 (Rap1), thus supporting LFA-1-mediated neutrophil adhesion. Importantly, with the use of Rac1 KO neutrophils, we could show that Rac1 acts upstream of Rap1. Our results establish HS1 as an important regulator of proper Rac1 and Rap1 activation and neutrophil extravasation.
Free Keywords:Abdominal Muscles/blood supply/cytology/immunology; Animals; Cell Adhesion/drug effects; Chemokine CXCL1/genetics/immunology/pharmacology; Chemotaxis/drug effects; Granulocyte Colony-Stimulating Factor/deficiency/genetics/*immunology; Immunity, Innate; Intravital Microscopy; Lymphocyte Function-Associated Antigen-1/genetics/*immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides/genetics/*immunology; Neutrophil Infiltration/drug effects; Neutrophils/drug effects/*immunology/pathology; Peritonitis/genetics/*immunology/pathology; Primary Cell Culture; rac1 GTP-Binding Protein/genetics/*immunology; rap1 GTP-Binding Proteins/genetics/*immunology; *adhesion; *inflammation; *integrins; *leukocyte extravasation; *transmigration
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department for Molecular Biomedicine, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico City, Mexico. Department for Molecular Biomedicine, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico City, Mexico mschnoor@cinvestav.mx. Department for Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Munster, Germany; and vestweb@mpi-muenster.mpg.de.
Identifiers:ISSN:1938-3673 (Electronic) 0741-5400 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28122813 [ID No:2]
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