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

Gaertner, Florian; Reis-Rodrigues, Patricia; Vries, Ingrid de; Hons, Miroslav; Aguilera, Juan; Riedl, Michael; Leithner, Alexander; Tasciyan, Saren; Kopf, Aglaja; Merrin, Jack; Zheden, Vanessa; Kaufmann, Walter A.; Hauschild, Robert; Sixt, Michael

doi:10.1016/j.devcel.2021.11.024

Cited by 53 publications

(49 citation statements)

References 92 publications

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“…Actin filament orientation is important for function, as myosin sliding along linear actin bundles for effective contraction requires a ring geometry with mixed actin filament polarities (Blanchoin et al, 2014; Cheffings et al, 2016). Our findings are also consistent with studies demonstrating a role for WASP in forming actin structures orthogonal to the cell’ s plasma membrane (Gaertner et al, 2022), as well as polarity during hemocyte (Stramer et al, 2005) and neutrophil (Brunetti et al, 2022) migration. Loss of branched actin also led to the formation of long linear actin filament bundles in the center of the wound.…”

Section: Discussionsupporting

confidence: 92%

Cell wound repair requires the coordinated action of linear and branched actin nucleation factors

Hui

Nakamura

Dubrulle

et al. 2022

Preprint

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Cells are subjected to a barrage of daily insults that often lead to its cortex being ripped open and requiring immediate repair. An important component of the cell′s repair response is the formation of an actomyosin ring at the wound periphery to mediate its closure. Inhibition of linear actin nucleation factors and myosin result in a disrupted contractile apparatus and delayed wound closure. Here we show that branched actin nucleators function as a scaffold to assemble and maintain this contractile actomyosin cable. Removing branched actin leads to the formation of smaller circular actin-myosin structures at the cell cortex and slow wound closure. Removing linear and branched actin results in failed wound closure. Surprisingly, removal of branched actin and myosin results in the formation of parallel linear actin filaments that undergo a chiral swirling movement to close the wound. These results provide insight into actin organization in contractile actomyosin rings and uncover a new mechanism of wound closure.

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Section: Discussionsupporting

confidence: 92%

Cell wound repair requires the coordinated action of linear and branched actin nucleation factors

Hui

Nakamura

Dubrulle

et al. 2022

Preprint

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“…Although the overall speed of both imDCs and mDCs was reduced, which is consistent with previous studies ( Extended data Fig. 10b ) 14,30–32 , the FP mode was absent, and the mean speed of both SD and SP modes was decreased significantly for both cases of myosin II and Arp2/3 inhibition ( Fig. 4d ).…”

supporting

confidence: 91%

Machine learning analysis reveals the dynamics of mode transition in dendritic cell migration

Song

Choi

Cho

2022

Preprint

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Dendritic cells (DCs) patrol the body as immunological sentinels and search for pathogens. Upon stimulation, immature DCs (imDCs) become mature DCs (mDCs), which migrate to the lymph nodes and present antigens to T cells. The migratory behavior is crucial for initiating and controlling immune responses; however, the properties of the highly heterogeneous and dynamic motility phenotype are not fully understood. Here, we established an unsupervised machine learning (ML) strategy to investigate spatiotemporal motility patterns in long-term, two-dimensional cell migration trajectories, and determined the number of motility patterns and how these are related to the maturation status. We identified three distinct migratory modes independent of the cell state: slow-diffusive (SD), slow-persistent (SP), and fast-persistent (FP). We found that maturation-dependent motility changes are emergent properties of the distribution and dynamic transitions of these three modes. Remarkably, imDCs changed their migration modes more frequently, and predominantly followed the SD→FP→SP→SD unicyclic transition, indicating that imDCs rapidly increase their speed during the shift from diffusive to persistent motility; however, persistence progressively declines when switching back to diffusive motility. In contrast, mDCs show no transition directionality. Our ML-promoted motility pattern analysis and history-dependent mode transition investigation may provide new insights into the complex process of biological motility.

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“…Arp2/3 complex activation in leukocytes is multi-faceted. The WAVE regulatory complex is fundamentally linked to traveling waves that drive lamellipodial protrusion and phagocytosis [ 62 , 63 , 64 ]. WASP, on the other hand, seems to have a more localized effect, exemplified by its role in podosome function [ 29 ] and endocytosis [ 30 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…WASP, on the other hand, seems to have a more localized effect, exemplified by its role in podosome function [ 29 ] and endocytosis [ 30 , 65 ]. WASP appears to respond to localized signals, including physical force and surface topography [ 62 , 66 ]. Despite these discrete contributions in some contexts, recent evidence also points to a role for both WAVE and WASP in pseudopod-based motility [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

The Actin Cytoskeleton Responds to Inflammatory Cues and Alters Macrophage Activation

Ronzier

Laurenson

Manickam

et al. 2022

Cells

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Much remains to be learned about the molecular mechanisms underlying a class of human disorders called actinopathies. These genetic disorders are characterized by loss-of-function mutations in actin-associated proteins that affect immune cells, leading to human immunopathology. However, much remains to be learned about how cytoskeletal dysregulation promotes immunological dysfunction. The current study reveals that the macrophage actin cytoskeleton responds to LPS/IFNγ stimulation in a biphasic manner that involves cellular contraction followed by cellular spreading. Myosin II inhibition by blebbistatin blocks the initial contraction phase and lowers iNOS protein levels and nitric oxide secretion. Conversely, conditional deletion of Arp2/3 complex in macrophages attenuates spreading and increases nitric oxide secretion. However, iNOS transcription is not altered by loss of myosin II or Arp2/3 function, suggesting post-transcriptional regulation of iNOS by the cytoskeleton. Consistent with this idea, proteasome inhibition reverses the effects of blebbistatin and rescues iNOS protein levels. Arp2/3-deficient macrophages demonstrate two additional phenotypes: defective MHCII surface localization, and depressed secretion of the T cell chemokine CCL22. These data suggest that interplay between myosin II and Arp2/3 influences macrophage activity, and potentially impacts adaptive-innate immune coordination. Disrupting this balance could have detrimental impacts, particularly in the context of Arp2/3-associated actinopathies.

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

Cited by 53 publications

References 92 publications

Cell wound repair requires the coordinated action of linear and branched actin nucleation factors

Cell wound repair requires the coordinated action of linear and branched actin nucleation factors

Machine learning analysis reveals the dynamics of mode transition in dendritic cell migration

The Actin Cytoskeleton Responds to Inflammatory Cues and Alters Macrophage Activation

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