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Published on: October 19, 2018
A mechanical bottleneck explains the variation in cup growth during FcgammaR phagocytosis
Jeroen S van Zon1, George Tzircotis, Emmanuelle Caron
1Centre for Integrative Systems Biology Imperial College (CISBIC), South Kensington Campus, Imperial College London, London, UK.
Insights
Phagocytosis, the process of cell engulfment, shows surprising variability in particle uptake. A mechanical bottleneck model explains why phagocytic cups stall or fully envelop particles, impacting immunity and development.
Area of Science:
- Cell biology
- Immunology
- Biophysics
Background:
- Phagocytosis is crucial for immunity, homeostasis, and development.
- It involves cells internalizing particulate material via a phagocytic cup.
- Fcgamma receptors (FcgammaRs) mediate the uptake of immunoglobulin G-coated particles.
Purpose of the Study:
- To investigate the variability in phagocytic cup formation during particle internalization.
- To understand the mechanical and biochemical factors governing phagocytic cup growth.
- To develop a model explaining the different fates of phagocytic cups.
Main Methods:
- Confocal microscopy to track fluorescently tagged FcgammaRs during cup growth.
- Experimental manipulation of F-actin concentration.
- Mathematical modeling of phagocytic cup growth dynamics.
Main Results:
- Phagocytic cups exhibited significant variability in growth around identical particles, even within the same cell.
- Cups showed two distinct outcomes: stalling before completion or successful full envelopment.
- Reduced F-actin levels did not consistently lead to stalled cups, contrary to simple force-based predictions.
Conclusions:
- A mechanical bottleneck model provides a coherent explanation for phagocytic uptake variability.
- Particle geometry significantly influences phagocytic uptake efficiency.
- The study offers a unifying framework for understanding the interplay of mechanical and biochemical processes in phagocytosis.
Abstract:
Phagocytosis is the process by which cells internalize particulate material, and is of central importance to immunity, homeostasis and development. Here, we study the internalization of immunoglobulin G-coated particles in cells transfected with Fcgamma receptors (FcgammaRs) through the formation of an enveloping phagocytic cup. Using confocal microscopy, we precisely track the location of fluorescently tagged FcgammaRs during cup growth. Surprisingly, we found that phagocytic cups growing around identical spherical particles showed great variability even within a single cell and exhibited two eventual fates: a cup either stalled before forming a half-cup or it proceeded until the particle was fully enveloped. We explain these observations in terms of a mechanical bottleneck using a simple mathematical model of the overall process of cup growth. The model predicts that reducing F-actin concentration levels, and hence the deforming force, does not necessarily lead to stalled cups, a prediction we verify experimentally. Our analysis gives a coherent explanation for the importance of geometry in phagocytic uptake and provides a unifying framework for integrating the key processes, both biochemical and mechanical, occurring during cup growth.
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