Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Mast cells

• Tissue-residency

• Actin remodelling

Main Findings

In this preprint, the authors investigate the role of actin remodelling on mast cell homeostasis. Based on previous observations integrin-dependent interactions with the actin cytoskeleton through Talin impact tissue-resident mast cells. To determine if further branching of the actin network is important in the maintenance of mast cells, the group generates Mcpt5-Cre x Arpc4fl/fl mice lacking the entire Arp2/3 actin remodelling complex specifically in mast cells. Using these and additional elegant tools (e.g. Ubow mice, Tln1fl/fl and Fast/Fucci) the authors demonstrate that Arp2/3 is critical for mast cell morphology, speed, proliferation and survival. Using primary human mast cells and human mast cell lines, the authors confirm their findings made in in animals. The author use an in vitro cell cycle tracking approach in WT and Arp2/3-deficient mast cells to demonstrate that actin remodelling is critical for mast cells to initiate proliferation and survive. Interestingly, the majority of the authors’ findings are observed when mast cells are exposed to an extracellular matrix, indicating the requirement for active interaction with their environment. Using antibody-mediated blockade or deletion of Talin, the authors’ verify that integrin-mediated adhesion to the extracellular matrix have to be followed by Arp2/3-mediated actin remodelling to maintain tissue-resident mast cell survival and proliferation. In summary, this preprint demonstrates that actin remodelling following interaction with the environment regulates mast cell survival and proliferation.

Limitations

• A central point remaining after their observation is the centred around the question on how the remodelled actin complex in tissue-resident mast cells promotes proliferation and survival? This becomes relevant when considering their data in the first figure. Is the elevated motility of mast cells causing cell death? Would a more “steady” interaction with the extracellular matrix be important for this process and which signals are downstream of the remodelling via Arp2/3?

• The authors demonstrate an accumulating effect on mast cell survival over the development of an animal. Would this be the consequence of a changing tissue environment in the developing skin or does Arp2/3 activity and expression differ in mast cells at these different time points of development?

• Another intriguing question arising from their data is whether Arp2/3 mediated remodelling is also involved in the maintenance of mast cells in other tissues?

• The authors beautifully demonstrate in several ways that integrin-dependent remodelling of the actin complex triggers pro-survival and proliferation in mast cells. How would abrogation of actin remodelling affect the response of an animal during a mast cell-dependent challenge? Could chemical inhibition of Arp2/3 or blockade of integrins improve anaphylaxis or food avoidance? In line with this, would a fibrotic tissue improve mast cell survival?

Significance/Novelty

What is the novelty of the preprint for the field specific?

The authors delineate a previously unknown role for integrin-mediate actin remodelling on mast cell survival and proliferation. They nicely demonstrate that distinct states of actin polymerization affect the survival, motility and proliferation of tissue-resident cells adding another piece to the puzzle in understanding the regulation and maintenance of mast cells within tissues.

How does the result of the preprint matter for general immunologists and/or patients?

This work reveals a previously underappreciated role for actin remodelling in maintaining tissue-resident cells. Considering that multiple tissue-resident immune cells interact with their environment, the authors finding inspire more detailed investigations into the role of integrin-mediated actin remodelling for the maintenance and survival of other tissue-resident immune cells.

Credit

Reviewed by Arthur Mortha (University of Toronto, Department of Immunology) as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interest in relation to their involvement in the review.