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

Summary

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.

Graphical abstract

Highlights

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  WASp drives cortical actin patch formation in response to mechanical load

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  Actin patches polymerize orthogonal to the plasma membrane

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  Actin patches locally push against obstacles to create space for locomotion

Abstract

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.