Force‐Induced α4 Integrin‐Dependent Monocyte Adhesion Strengthening and F‐Actin Remodeling Requires Actomyosin Contractility and Talin‐1
Bibliographic record
Abstract
During inflammation, monocytes roll and arrest on inflamed endothelium, at which point they are subjected to increased hydrodynamic forces imparted by the flowing blood. We showed previously that stabilization of α4 integrin‐mediated monocyte adhesion and resistance to detachment involves rapid actin polymerization and accumulation of filamentous actin (F‐actin) at upstream adhesion sites and in the adjacent cortical actin cytoskeleton (J Cell Biol 2012; 197:115–129). Using parallel plate flow chamber assays with a VCAM‐1‐coated adhesion surface, U937 monocyte‐like cell line and confocal imaging we further investigated mechanisms of adhesion strengthening and actin cytoskeleton dynamics in cells undergoing α4 integrin‐mediated adhesion. Myosin ATPase, calcium/calmodulin, myosin light chain kinase and Rho kinase signaling were required for α4 integrin‐mediated adhesion strengthening in the presence of hydrodynamic force. Upon introduction of fluid flow (2 dynes/cm 2 ), adherent U937 cells flattened and the cell contact area with the adhesion surface increased both parallel and perpendicular to the direction of fluid flow. In addition, F‐actin at the adhesion surface redistributed towards the periphery of the adhesion surface contact area. Increased cell adhesion surface contact area and F‐actin redistribution were highly reproducible responses observed in >90% of adherent cells. Unlike F‐actin, α4 integrins remained localized throughout the adhesion contact area, and formed clusters in response to flow. Inhibition of myosin ATPase prevented force‐induced lateral spreading of U937 cells and F‐actin redistribution at the adhesion surface. siRNA knockdown of talin‐1, an adaptor molecule that binds to the integrin β‐chain cytoplasmic tail and mediates outside‐in‐signaling as well as interaction with the actin cytoskeleton, also inhibited α4 integrin‐dependent adhesion stabilization, lateral spreading and redistribution of F‐actin. These data suggest that integrin‐dependent adhesion stabilization and cytoskeletal remodeling induced by hydrodynamic force require both actomyosin contraction and talin‐1. When U937 cells were adhered to poly‐L‐lysine, we observed that hydrodynamic force induced a similar increase in the cell adhesion surface contact area and F‐actin redistribution; however, in this setting neither myosin ATPase nor talin‐1 were required. This suggests that adherent cells can respond to hydrodynamic force in an integrin‐independent manner, but adhesion mediated by α4 integrins inhibits the force‐induced, integrin‐independent response. Support or Funding Information Funded by CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".