Intermittent rolling is a defect of the extravasation cascade caused by Myosin1e-deficiency in neutrophils
Eduardo Vadillo1, Sandra Chánez-Paredes1, Hilda Vargas-Robles1
1Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), San Pedro Zacatenco, 07360 Mexico City, Mexico.
Abstract:
Neutrophil extravasation is a migratory event in response to inflammation that depends on cytoskeletal dynamics regulated by myosins. Myosin-1e (Myo1e) is a long-tailed class-I myosin that has not yet been studied in the context of neutrophil-endothelial interactions and neutrophil extravasation. Intravital microscopy of TNFα-inflamed cremaster muscles in Myo1e-deficient mice revealed that Myo1e is required for efficient neutrophil extravasation. Specifically, Myo1e deficiency caused increased rolling velocity, decreased firm adhesion, aberrant crawling, and strongly reduced transmigration. Interestingly, we observed a striking discontinuous rolling behavior termed "intermittent rolling," during which Myo1e-deficient neutrophils showed alternating rolling and jumping movements. Surprisingly, chimeric mice revealed that these effects were due to Myo1e deficiency in leukocytes. Vascular permeability was not significantly altered in Myo1e KO mice. Myo1e-deficient neutrophils showed diminished arrest, spreading, uropod formation, and chemotaxis due to defective actin polymerization and integrin activation. In conclusion, Myo1e critically regulates adhesive interactions of neutrophils with the vascular endothelium and neutrophil extravasation. Myo1e may therefore be an interesting target in chronic inflammatory diseases characterized by excessive neutrophil recruitment.
Insights
Myosin-1e (Myo1e) is crucial for neutrophil extravasation, the process of immune cells migrating to sites of inflammation. Myo1e deficiency impairs neutrophil adhesion and transmigration, highlighting its role in inflammatory diseases.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Neutrophil extravasation is vital for inflammatory responses.
- Cytoskeletal dynamics, regulated by myosins, are essential for this process.
- The role of Myosin-1e (Myo1e) in neutrophil-endothelial interactions was previously unstudied.
Purpose of the Study:
- To investigate the role of Myosin-1e (Myo1e) in neutrophil extravasation.
- To determine the cellular mechanisms underlying Myo1e's function in neutrophil migration.
Main Methods:
- Intravital microscopy in TNFα-inflamed cremaster muscles of Myo1e-deficient mice.
- Analysis of neutrophil behavior, including rolling, adhesion, and transmigration.
- Chimeric mouse models to assess cell-specific Myo1e function.
Main Results:
- Myo1e is essential for efficient neutrophil extravasation.
- Myo1e deficiency led to increased rolling velocity, decreased firm adhesion, and reduced transmigration.
- A novel "intermittent rolling" behavior was observed in Myo1e-deficient neutrophils.
- Defects in actin polymerization and integrin activation were observed in Myo1e-deficient neutrophils.
- Myo1e deficiency in leukocytes, not endothelial cells, caused these effects.
Conclusions:
- Myosin-1e critically regulates neutrophil adhesion to the endothelium and their extravasation.
- Myo1e plays a significant role in neutrophil recruitment during inflammation.
- Myo1e represents a potential therapeutic target for inflammatory diseases with excessive neutrophil infiltration.
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