Interstitial leukocyte navigation through a search and run response to gradients

Abstract

Migrating cells must interpret chemical gradients to guide themselves within tissues. A general premise has been that gradients influence the direction of leading-edge protrusions. However, recent evidence indicates that actin flows correlate better with directed motion than protrusions. A unified chemotaxis model that integrates the role of protrusions and actin flows and that accounts for in vivo cell motion patterns is lacking. Here, we provide direct experimental evidence of how neutrophils sense gradients in real-time in vivo and demonstrate a two-stage process: first a "search" phase, that requires actin network expansion by Arp2/3, whereby cells slow down, explore the environment and execute path corrections. This is followed by a "run" phase, that requires Myosin-II-driven contractility and fast actin flows, whereby cells accelerate and persist in the source direction. Thus, protrusive forces support chemotaxis by enhancing signal detection, while actin flows act as the ultimate output of gradient processing.

Macrophage network dynamics depend on haptokinesis for optimal local surveillance

“…The effects of cytochalasin D and Y27632 treatment on chemotactic macrophage migration were comparable to our previous results on random motility ( Figure 1C–E ), showing an essential requirement for actin dynamics and an important role for actomyosin contraction ( Figure 3B, D and E ). CK-666 treatment did not impair BMDM chemotaxis in 3D matrigel ( Figure 3—figure supplement 1 ), which is in agreement with previous studies showing that Arp2/3 complex blockade rather increases than decreases migration speed in several cell types ( Asokan et al, 2014 ; Dimchev et al, 2021 ; Georgantzoglou et al, 2021 ; Leithner et al, 2016 ; Moreau et al, 2015 ; Rotty et al, 2017 ; Vargas et al, 2016 ; Wu et al, 2012 ). Strikingly, the dependency on integrin function was markedly different between random and chemotactic macrophage migration.…”

“…In contrast, macrophage movement in 3D matrigels strictly depends on β1 integrin-mediated mechanotransduction, causing a substantial migration defect upon Arp2/3 complex inhibition. Yet, movement of CK-666-treated macrophages along a strong chemotactic gradient was unimpaired, which is in agreement with several previous studies on fibroblasts ( Asokan et al, 2014 ; Dimchev et al, 2021 ; Wu et al, 2012 ), BMDMs ( Rotty et al, 2017 ), and other immune cell types ( Georgantzoglou et al, 2021 ; Leithner et al, 2016 ; Moreau et al, 2015 ; Vargas et al, 2016 ), supporting the general notion that dendritic actin networks rather inhibit than support persistent movement along chemotactic cues and in confined environments. As seen for low-adhesive neutrophils and dendritic cells ( Georgantzoglou et al, 2021 ; Leithner et al, 2016 ), macrophages also rely on Arp2/3-mediated front actin networks for space exploration in complex environments.…”

Macrophage network dynamics depend on haptokinesis for optimal local surveillance

“…The effects of cytochalasin D and Y27632 treatment on chemotactic macrophage migration were comparable to our previous results on random motility (Figures 1C–1E), showing an essential requirement for actin dynamics and an important role for actomyosin contraction (Figures 3B, 3D and 3E). CK-666 treatment did not impair BMDM chemotaxis in 3D matrigel (Figure 3 – figure supplement 1), which is in agreement with previous studies showing that Arp2/3 complex blockade rather increases than decreases migration speed in several cell types (Asokan et al, 2014; Dimchev et al, 2021; Georgantzoglou et al, 2021; Leithner et al, 2016; Moreau et al, 2015; Rotty et al, 2017; Vargas et al, 2016; Wu et al, 2012). Strikingly, the dependency on integrin function was markedly different between random and chemotactic macrophage migration.…”

“…In contrast, macrophage movement in 3D matrigels strictly depends on β1 integrin-mediated mechanotransduction, causing a substantial migration defect upon Arp2/3 complex inhibition. Yet, movement of CK-666 treated macrophages along a strong chemotactic gradient was unimpaired, which is in agreement with several previous studies on fibroblasts (Asokan et al, 2014; Dimchev et al, 2021; Wu et al, 2012), BMDMs (Rotty et al, 2017) and other immune cell types (Georgantzoglou et al, 2021; Leithner et al, 2016; Moreau et al, 2015; Vargas et al, 2016), supporting the general notion that dendritic actin networks rather inhibit than support persistent movement along chemotactic cues and in confined environments. As seen for low-adhesive neutrophils and dendritic cells (Georgantzoglou et al, 2021; Leithner et al, 2016), macrophages also rely on Arp2/3-mediated front actin networks for space exploration in complex environments.…”

“…However, macrophages strictly depend on integrin-mediated ECM interactions to establish lamellopodial protrusions as exploratory structures. Their directed movement towards strong chemotactic gradients does not require integrins or Arp2/3, which is reminiscent of cell types that perform amoeboid migration, where persistent locomotion depends on actin flow and actomyosin contraction (Georgantzoglou et al, 2021; Leithner et al, 2016).…”