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The zipper mechanism in phagocytosis: energetic requirements and variability in phagocytic cup shape.

Tollis S, Dart AE, Tzircotis G, Endres RG - BMC Syst Biol (2010)

Bottom Line: Highly curved shapes are not taken up, in line with recent experimental results.This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles.The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Biosciences, South Kensington Campus, Imperial College London, SW72AZ London, UK.

ABSTRACT

Background: Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by their cell membrane. Particle engulfment involves particle recognition by cell-surface receptors, signaling and remodeling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. Despite the signaling complexity, phagocytosis also depends strongly on biophysical parameters, such as particle shape, and the need for actin-driven force generation remains poorly understood.

Results: Here, we propose a novel, three-dimensional and stochastic biophysical model of phagocytosis, and study the engulfment of particles of various sizes and shapes, including spiral and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not taken up, in line with recent experimental results. Furthermore, we surprisingly find that even without actin-driven force generation, engulfment proceeds in a large regime of parameter values, albeit more slowly and with highly variable phagocytic cups. We experimentally confirm these predictions using fibroblasts, transfected with immunoreceptor FcγRIIa for engulfment of immunoglobulin G-opsonized particles. Specifically, we compare the wild-type receptor with a mutant receptor, unable to signal to the actin cytoskeleton. Based on the reconstruction of phagocytic cups from imaging data, we indeed show that cells are able to engulf small particles even without support from biological actin-driven processes.

Conclusions: This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles. The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.

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Engulfment simulations of active and passive zippers. (A) Side view (top) and cross section (bottom) of a phagocytic cup obtained for the active zipper. (B) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and percentage of engulfment, defined by the average membrane height around the particle (blue solid, blue dashed, blue dotted lines) for three repeats of the stochastic simulation. (C) Side view (top) and cross section (bottom) of the phagocytic cup obtained for the passive zipper (same overall simulation time). (D) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and engulfment (blue solid, blue dashed, blue dotted lines) for three repeats of the simulation. Dashed light blue line indicates corresponding maximal membrane height for one of the simulations (in percentage of the particle diameter). Small particles with 1.5 μm radius were used.
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Figure 3: Engulfment simulations of active and passive zippers. (A) Side view (top) and cross section (bottom) of a phagocytic cup obtained for the active zipper. (B) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and percentage of engulfment, defined by the average membrane height around the particle (blue solid, blue dashed, blue dotted lines) for three repeats of the stochastic simulation. (C) Side view (top) and cross section (bottom) of the phagocytic cup obtained for the passive zipper (same overall simulation time). (D) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and engulfment (blue solid, blue dashed, blue dotted lines) for three repeats of the simulation. Dashed light blue line indicates corresponding maximal membrane height for one of the simulations (in percentage of the particle diameter). Small particles with 1.5 μm radius were used.

Mentions: Figure 3 (left) shows that engulfment of small (1.5 μm radius) particles by the passive zipper leads to more variable phagocytic cup shapes than engulfment by the active zipper. For the active zipper, random membrane fluctuations are rectified by irreversible ligand-receptor binding due to actin polymerization. This leads to uniform progression of the cell membrane all around the particle at approximately the same speed (Figure 3A). In contrast, engulfment by the passive zipper occurs through binding of large membrane ruffles which eventually enclose the particle (Figure 3C). The variability of the phagocytic cup may be a measure of the respective contributions of active and passive processes in engulfment progression.


The zipper mechanism in phagocytosis: energetic requirements and variability in phagocytic cup shape.

Tollis S, Dart AE, Tzircotis G, Endres RG - BMC Syst Biol (2010)

Engulfment simulations of active and passive zippers. (A) Side view (top) and cross section (bottom) of a phagocytic cup obtained for the active zipper. (B) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and percentage of engulfment, defined by the average membrane height around the particle (blue solid, blue dashed, blue dotted lines) for three repeats of the stochastic simulation. (C) Side view (top) and cross section (bottom) of the phagocytic cup obtained for the passive zipper (same overall simulation time). (D) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and engulfment (blue solid, blue dashed, blue dotted lines) for three repeats of the simulation. Dashed light blue line indicates corresponding maximal membrane height for one of the simulations (in percentage of the particle diameter). Small particles with 1.5 μm radius were used.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991294&req=5

Figure 3: Engulfment simulations of active and passive zippers. (A) Side view (top) and cross section (bottom) of a phagocytic cup obtained for the active zipper. (B) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and percentage of engulfment, defined by the average membrane height around the particle (blue solid, blue dashed, blue dotted lines) for three repeats of the stochastic simulation. (C) Side view (top) and cross section (bottom) of the phagocytic cup obtained for the passive zipper (same overall simulation time). (D) Corresponding time courses of the membrane energy (thick solid, medium dashed and thin dotted black lines) and engulfment (blue solid, blue dashed, blue dotted lines) for three repeats of the simulation. Dashed light blue line indicates corresponding maximal membrane height for one of the simulations (in percentage of the particle diameter). Small particles with 1.5 μm radius were used.
Mentions: Figure 3 (left) shows that engulfment of small (1.5 μm radius) particles by the passive zipper leads to more variable phagocytic cup shapes than engulfment by the active zipper. For the active zipper, random membrane fluctuations are rectified by irreversible ligand-receptor binding due to actin polymerization. This leads to uniform progression of the cell membrane all around the particle at approximately the same speed (Figure 3A). In contrast, engulfment by the passive zipper occurs through binding of large membrane ruffles which eventually enclose the particle (Figure 3C). The variability of the phagocytic cup may be a measure of the respective contributions of active and passive processes in engulfment progression.

Bottom Line: Highly curved shapes are not taken up, in line with recent experimental results.This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles.The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Biosciences, South Kensington Campus, Imperial College London, SW72AZ London, UK.

ABSTRACT

Background: Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by their cell membrane. Particle engulfment involves particle recognition by cell-surface receptors, signaling and remodeling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. Despite the signaling complexity, phagocytosis also depends strongly on biophysical parameters, such as particle shape, and the need for actin-driven force generation remains poorly understood.

Results: Here, we propose a novel, three-dimensional and stochastic biophysical model of phagocytosis, and study the engulfment of particles of various sizes and shapes, including spiral and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not taken up, in line with recent experimental results. Furthermore, we surprisingly find that even without actin-driven force generation, engulfment proceeds in a large regime of parameter values, albeit more slowly and with highly variable phagocytic cups. We experimentally confirm these predictions using fibroblasts, transfected with immunoreceptor FcγRIIa for engulfment of immunoglobulin G-opsonized particles. Specifically, we compare the wild-type receptor with a mutant receptor, unable to signal to the actin cytoskeleton. Based on the reconstruction of phagocytic cups from imaging data, we indeed show that cells are able to engulf small particles even without support from biological actin-driven processes.

Conclusions: This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles. The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.

Show MeSH
Related in: MedlinePlus