TNF induces neutrophil adhesion via formin-dependent cytoskeletal reorganization and activation of β-integrin function
| Autor: | Wilson A. Ferreira, Camila B. Almeida, Cristina P. Vicente, Venina Marcela Dominical, Fernando Ferreira Costa, Nicola Conran, Fabio T. M. Costa, Angélica Aparecida Antoniellis Silveira, Hanan Chweih, Claudio C. Werneck |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Fetal Proteins Male 0301 basic medicine RHOA Adolescent Neutrophils Immunology Formins Inflammation Mice Young Adult 03 medical and health sciences chemistry.chemical_compound Cell Adhesion medicine Animals Humans Immunology and Allergy Cytoskeleton Rho-associated protein kinase Cells Cultured Cytochalasin D Actin nucleation biology Tumor Necrosis Factor-alpha Microfilament Proteins Nuclear Proteins Cell Biology Middle Aged Cell biology Mice Inbred C57BL Actin Cytoskeleton 030104 developmental biology chemistry CD18 Antigens biology.protein Tumor necrosis factor alpha medicine.symptom rhoA GTP-Binding Protein Signal Transduction |
| Zdroj: | Journal of Leukocyte Biology. 103:87-98 |
| ISSN: | 1938-3673 0741-5400 |
| Popis: | Although essential for inflammatory responses, leukocyte recruitment to blood vessel walls in response to inflammatory stimuli, such as TNF-α, can contribute to vascular occlusion in inflammatory diseases, including atherosclerosis. We aimed to further characterize the mechanisms by which TNF stimulates adhesive and morphologic alterations in neutrophils. Microfluidic and intravital assays confirmed the potent effect that TNF has on human and murine neutrophil adhesion and recruitment in vitro and in vivo, respectively. Inhibition of actin polymerization by cytochalasin D significantly diminished TNF-induced human neutrophil adhesion in vitro and abolished TNF-induced membrane alterations and cell spreading. In contrast, TNF-induced increases in β2-integrin (Mac-1 and LFA-1) expression was not significantly altered by actin polymerization inhibition. Consistent with a role for cytoskeletal rearrangements in TNF-induced adhesion, TNF augmented the activity of the Rho GTPase, RhoA, in human neutrophils. However, inhibition of the major RhoA effector protein, Rho kinase (ROCK), by Y-27632 failed to inhibit TNF-induced neutrophil adhesion. In contrast, the formin FH2 domain inhibitor, SMIFH2, abolished TNF-induced human neutrophil adhesion and diminished leukocyte recruitment in vivo. SMIFH2 also inhibited TNF-induced cytoskeletal reorganization in human neutrophils and abolished the alterations in β2-integrin expression elicited by TNF stimulation. As such, Rho GTPase/mDia formin-mediated cytoskeletal reorganization appears to participate in the orchestration of TNF-induced neutrophil-adhesive interactions, possibly mediated by formin-mediated actin nucleation and subsequent modulation of β2-integrin activity on the neutrophil surface. This pathway may represent a pharmacologic target for reducing leukocyte recruitment in inflammatory diseases. |
| Databáze: | OpenAIRE |
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