The Freeman Lab
The Freeman Lab
Our Research

Cells are the smallest independent units of plants and animals. Virtually all human organs and tissues have specialized, sentinel cells (macrophages) that are dedicated to protecting the body from infection, damage, or toxins. To detect signs of a threat, macrophages probe and survey their locale using sensors that distinguish harmful from healthy components.

Because some threats can be well-hidden, they internalize and digest massive quantities of their surroundings to expose such threats internally. Once swallowed, the ingested materials are sealed in a vacuole, digested, and probed for any signs of harm. These later steps require the evolution of the vacuole to acquire degradative enzymes, acidify, and distribute the contents to internal detectors.

microscope images showing fluorescent glucose analog
2-NDBG (green) is a fluorescent glucose analog. Macrophages (cyan) drink glucose and much larger molecules from the extracellular fluid like dextrans (red). They trap these volumes to survey their surroundings. Signaling that directs immune responses often emanates from these sealed vacuoles (yellow).

We are interested in two overlooked aspects to immune surveillance by macrophages:

First, the consumption and catabolism performed by macrophages is remarkable; they take up their own body weight in just a matter of hours. An essential part of the whole process is that these large volumes must be resolved in order for the cells to maintain their responsiveness. We are working on how the resolution process is orchestrated by transporters that expel the smallest components of the ingested medium out of the vacuole and cell.

A big part of our research seeks to understand how the resolution of digested samples by macrophages is regulated, and why alterations in its regulation cause these cells to contribute to diseases rather than correct it.

Since all forms of endocytosis involve the ingestion of fluid, understanding the basic principles of solute fluxes that move fluid in cells will broadly contribute to the field of membrane trafficking.

smallest components of ingested medium (ion) are expelled from vacuoles
The smallest components of ingested medium (ion) are expelled from vacuoles. Water follows. The vacuole is then remodelled and ultimately resolved. This is critical in maintaining the responsiveness of the cell.

Second, macrophages scan their neighbours for signals that initiate phagocytosis and are repelled by the “don’t eat me” signals of healthy cells. The “don’t eat me” signals engage inhibitory receptors that arrest signaling pathways by recruiting otherwise cytosolic phosphatases that suppress phagocytosis. In anti-inflammatory contexts, cytokines mediate the transcriptional upregulation of these inhibitory receptors.

Certain tumors have found ways to usurp these mechanisms to evade the immune response and support their growth by ultimately inhibiting phagocytosis and the presentation of neo-antigens.

Since phagocytosis is a tunable and translationally impactful process, dependent on the features of the target and the microenvironment of the phagocyte, understanding the mechanisms that modulate receptor activation is of great importance.

We are looking for talented people to join our team!

Have a look at our projects and if they sound interesting to you, please contact us.

Special thanks to our funding!

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