The mechanism of phagocytosis: two stages of engulfment

TL;DR

This study reveals that phagocytosis occurs in two stages with distinct mechanisms, involving passive receptor diffusion initially and active regulation later, and introduces models predicting optimal ligand density and particle shape for efficient engulfment.

Contribution

The paper provides the first detailed analysis of the two-stage process of phagocytosis and introduces models explaining the dynamics and factors influencing engulfment efficiency.

Findings

Phagocytosis occurs in two distinct stages with different rates.

Passive receptor diffusion dominates the initial stage.

Active regulation accelerates engulfment after half-completion.

Abstract

Despite being of vital importance to the immune system, the mechanism by which cells engulf relatively large solid particles during phagocytosis is still poorly understood. From movies of neutrophil phagocytosis of polystyrene beads, we measure the fractional engulfment as a function of time and demonstrate that phagocytosis occurs in two distinct stages. During the first stage, engulfment is relatively slow and progressively slows down as phagocytosis proceeds. However, at approximately half-engulfment, the rate of engulfment increases dramatically, with complete engulfment attained soon afterwards. By studying simple mathematical models of phagocytosis, we suggest that the first stage is due to a passive mechanism, determined by receptor diffusion and capture, whereas the second stage is more actively controlled, perhaps with receptors being driven towards the site of engulfment. We then consider a more advanced model that includes signaling and captures both stages of engulfment. This model predicts that there is an optimum ligand density for quick engulfment. Further, we show how this model explains why non-spherical particles engulf quickest when presented tip-first. Our findings suggest that active regulation may be a later evolutionary innovation, allowing fast and robust engulfment even for large particles.