Intermittent rolling is a defect of the extravasation cascade caused by Myosin1e-deficiency in neutrophils

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.

Long-Tailed Unconventional Class I Myosins in Health and Disease

“…The impaired neutrophil migration observed in MYO1E-and MYO1F-deficient mice have distinct molecular foundations. In the case of MYO1F, its absence did not lead to reduced neutrophil rolling or adhesion on endothelial cells, a phenomenon that was described in MYO1E-deficient neutrophils [27]. MYO1F-mediated neutrophil migration has been reported to be critical to acute neuroinflammation in ischemic stroke, directly affecting outcomes.…”

“…Although MYO1E is barely expressed in neutrophils, it has been shown to be required for their efficient extravasation [27]. Recently, MYO1E-deficient neutrophils were shown to have diminished arrest, spreading, uropod formation, and chemotaxis due to defective actin polymerization and integrin activation.…”

“…This phenotype resulted in increased rolling velocity, decreased firm adhesion, aberrant crawling, and strongly reduced transmigration. Thus, MYO1E appears to regulate the adhesive interactions of neutrophils with the vascular endothelium needed for neutrophil extravasation, reducing both 2D and 3D migration [27].…”

Editorial: Evolution, Emerging Functions and Structure of Actin-Binding Proteins

“…Absence of both myosins significantly impairs actin-dependent phagocytic cup formation and clearance of pathogens. Myo1e is also important for actin polymerization and integrin clustering in neutrophils during extravasation (Vadillo et al, 2019). These are only a few examples highlighting the important cell biological functions of ABPs in different pathophysiological contexts.…”

“…These are only a few examples highlighting the important cell biological functions of ABPs in different pathophysiological contexts. With newly identified biochemical and biological properties of ABPs, they have been considered as important targets in treating diseases (Yin et al, 2018b;Vadillo et al, 2019;Yin et al, 2019). This special issue contains 31 original and review papers, that discuss the recent advances in our knowledge about ABPs and their various biological processes.…”