Target cell tension regulates macrophage trogocytosis

Caitlin E. Cornell, Aymeric Chorlay, Deepak Krishnamurthy, Nicholas R. Martin, Lucia Baldauf, Daniel A. Fletcher

Posted on: 4 January 2025 , updated on: 6 January 2025

Preprint posted on 5 December 2024

Feeling tense? Macrophages sense that! Macrophages prefer to "nibble" (trogocytose) soft targets and "engulf" (phagocytose) stiff ones. Stiffness matters for immune responses!

Selected by Felipe Del Valle Batalla

Categories: biophysics, cancer biology, cell biology, immunology

Background

Macrophages are immune cells known for engulfing and destroying harmful agents like bacteria and cancer cells through phagocytosis (1). However, macrophages can also engage in a more obscure process called trogocytosis, where they extract small membrane pieces from targets instead of completely engulfing them. In this preprint, the authors propose that the physical properties of target cells play in determining whether macrophages “nibble” or “engulf” them.

Key findings

This preprint demonstrates that target cell stiffness, specifically cortical tension, plays a crucial role in the macrophage decision-making process between trogocytosis of phagocytosis:

Softer targets get nibbled: Using a flow cytometry assay with fluorescent labeling to distinguish between trogocytosis and phagocytosis, the researchers found that softer cancer cells (Jurkat T cells) undergo trogocytosis more often by RAW 264.7 macrophages (Fig 1). They directly measured cell stiffness (cortical tension) with micropipette aspiration, applying controlled suction to deform the cell membrane and calculating their cortical tension.
Stiffer targets get engulfed: Conversely, stiffer cancer cells (HL60s) with higher cortical tension were more likely to be phagocytosed (Fig 2), supporting the concept that target stiffness guides macrophage behavior. To further test this, the authors chemically stiffened target cells (Jurkat T cells and HL60s) using glutaraldehyde. This treatment increased cortical tension, as confirmed by micropipette aspiration. Flow cytometry analysis then showed that stiffening significantly suppressed trogocytosis while promoting phagocytosis.
A model for nibbling vs. engulfing: The authors propose a model of decision-making between trogocytosis and phagocytosis that considers the balance between the active forces exerted by macrophages and the resisting cortical tension of the target cell. This model predicts a critical antibody density needed for trogocytosis. It suggests that a minimum antibody density is required to overcome the stiffness of the target and allow the macrophage to extract membrane bits (Fig 5).

What makes this work important

This research provides compelling evidence that physical properties, particularly target stiffness, influence macrophage behavior. Personally, it also feels interesting since mechanosensing-related cell behavior is a promising area that could be exploited to shape the immune response and develop new therapies. Finally, this work suggests that trogocytosis might be much more common than previously thought, especially when macrophages encounter softer targets like cells.

Future directions and questions for the authors:

The study focused on cancer cells. How does target stiffness influence trogocytosis versus phagocytosis with other targets, such as bacteria known to have a wide range of stiffness?
Could tumor cells evolve to become softer to evade phagocytosis by promoting trogocytosis?
Could therapies that stiffen tumor cells make them more susceptible to destruction by macrophages?
In this study, the size of target cells and vesicles are smaller than the macrophages. Could the mechanical model be refined to consider other factors like target cell shape and size?

References

(1) Chen, S., Saeed, A.F., Liu, Q. et al.Macrophages in immunoregulation and therapeutics. Sig Transduct Target Ther 8, 207 (2023). https://doi.org/10.1038/s41392-023-01452-1

doi: https://doi.org/10.1242/prelights.39333

Read preprint