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Publications of the Week

Fetal Origin Confers Radio-Resistance on Liver Macrophages via p21cip1/WAF1

By May 28, 2019June 3rd, 2019No Comments

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This week we profile a recent publication in the Journal of Hepatology from the laboratory of Dr. Ian Crispe
(pictured, left) at the University of Washington Departments of Pathology and Immunology.

Can you provide a brief overview of your lab’s current research focus?

Our lab is focused on immune responses in the liver. In this organ, innate immunity is very active but T cell immunity is dialed way down, probably because the liver is constantly exposed to new molecules and it would cause disease to have the T cells firing off every time you eat a new food (or a new food additive). But this safety mechanism, called liver tolerance, opens a window of vulnerability that viruses and parasites have evolved to exploit. The mission of the lab is to identify the cellular and molecular mechanisms that account for liver tolerance. As a counterpoint, we also want to know how innate immune responses work in the liver, and how these may either resist or participate in disease.

What is the significance of the findings in this publication?

There is a widely-held idea that tissue macrophages are shaped mostly by the tissue in which they find themselves, and in the case of Kupffer cells, this is the liver. However, our work recently published in the Journal of Hepatology shows that the origin of the cells also strongly influences how they respond to stress. In our experiments, the stress was radiation, and the Kupffer cells that originated from precursors in the fetus survived it much better than Kupffer cells that originated in the adult bone marrow. This was because the cells of fetal origin could shut down cell division by expressing a protein that causes cell cycle arrest. This may be helpful in devising clinical counter-measures against radiation-induced immune failure.

What are the next steps for this research?

The next steps in this work will be to determine if the rule that macrophages of very early origin are resistant to radiation is true in other tissues. So, we will test this in the heart, and in the lung. If the theory hold up, we’ll start inventing ways to make the non-fetal macrophages more radio-resistant. This may lead to new approaches for treating radiation exposure.

This work was funded by:

The work was supported by the NIAID and the American Heart Association.

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