WASp triggers mechanosensitive actin patches to facilitate immune cell migration in dense tissues

• Published in: Developmental cell Vol. 57; no. 1; pp. 47 - 62.e9
• Main Authors: Gaertner, Florian, Reis-Rodrigues, Patricia, de Vries, Ingrid, Hons, Miroslav, Aguilera, Juan, Riedl, Michael, Leithner, Alexander, Tasciyan, Saren, Kopf, Aglaja, Merrin, Jack, Zheden, Vanessa, Kaufmann, Walter Anton, Hauschild, Robert, Sixt, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-01-2022; Cell Press
• Subjects: actin cytoskeleton; Actin-Related Protein 2-3 Complex - metabolism; Actin-Related Protein 2-3 Complex - physiology; Actin-Related Protein 3 - metabolism; Actins - metabolism; Actins - physiology; ameboid motility; Animals; Biomechanical Phenomena - physiology; Cell Line; cell migration; Cell Movement - physiology; confinement; Cytoskeletal Proteins - metabolism; dendritic cells; Female; leukocytes; Leukocytes - physiology; Male; mechanical load; mechanosensing; Mice; Mice, Inbred C57BL; Protein Binding - physiology; T cells; Wiskott-Aldrich syndrome protein; Wiskott-Aldrich Syndrome Protein - genetics; Wiskott-Aldrich Syndrome Protein - metabolism; actin cytoskeleton; Wiskott-Aldrich syndrome protein; mechanosensing; dendritic cells; confinement; ameboid motility; cell migration; leukocytes; mechanical load; T cells
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2021.11.024

When crawling through the body, leukocytes often traverse tissues that are densely packed with extracellular matrix and other cells, and this raises the question: How do leukocytes overcome compressive mechanical loads? Here, we show that the actin cortex of leukocytes is mechanoresponsive and that this responsiveness requires neither force sensing via the nucleus nor adhesive interactions with a substrate. Upon global compression of the cell body as well as local indentation of the plasma membrane, Wiskott-Aldrich syndrome protein (WASp) assembles into dot-like structures, providing activation platforms for Arp2/3 nucleated actin patches. These patches locally push against the external load, which can be obstructing collagen fibers or other cells, and thereby create space to facilitate forward locomotion. We show in vitro and in vivo that this WASp function is rate limiting for ameboid leukocyte migration in dense but not in loose environments and is required for trafficking through diverse tissues such as skin and lymph nodes.
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•WASp drives cortical actin patch formation in response to mechanical load•Actin patches polymerize orthogonal to the plasma membrane•Actin patches locally push against obstacles to create space for locomotion
Gaertner et al. demonstrate that the actin cortex of immune cells is sensitive to mechanical load. In response to cellular indentation, Wiskott-Aldrich syndrome protein (WASp) triggers the formation of actin patches that polymerize orthogonal to the plasma membrane. Actin patches generate local pushing forces facilitating forward locomotion in obstructive tissues.