Skip to main content

macrophage

Replenishing the Liver’s Immune Protections

Posted on by

Kupffer cells
Credit: Thomas Deerinck, National Center for Microscopy and Imaging Research, University of California, San Diego.

Most of our immune cells circulate throughout the bloodstream to serve as a roving security force against infection. But some immune cells don’t travel much at all and instead safeguard a specific organ or tissue. That’s what you are seeing in this electron micrograph of a type of scavenging macrophage, called a Kupffer cell (green), which resides exclusively in the liver (brown).

Normally, Kupffer cells appear in the liver during the early stages of mammalian development and stay put throughout life to protect liver cells, clean up old red blood cells, and regulate iron levels. But in their experimental system, Christopher Glass and his colleagues from University of California, San Diego, removed all original Kupffer cells from a young mouse to see if this would allow signals from the liver that encourage the development of new Kupffer cells.

The NIH-funded researchers succeeded in setting up the right conditions to spur a heavy influx of circulating precursor immune cells, called monocytes, into the liver, and then prompted those monocytes to turn into the replacement Kupffer cells. In a recent study in the journal Immunity, the team details the specific genomic changes required for the monocytes to differentiate into Kupffer cells [1]. This information will help advance the study of Kupffer cells and their role in many liver diseases, including nonalcoholic steatohepatitis (NASH), which affects an estimated 3 to 12 percent of U.S. adults [2].

The new work also has broad implications for immunology research because it provides additional evidence that circulating monocytes contain genomic instructions that, when activated in the right way by nearby cells or other factors, can prompt the monocytes to develop into various, specialized types of scavenging macrophages. For example, in the mouse system, Glass’s team found that the endothelial cells lining the liver’s blood vessels, which is where Kupffer cells hang out, emit biochemical distress signals when their immune neighbors disappear.

While more details need to be worked out, this study is another excellent example of how basic research, including the ability to query single cells about their gene expression programs, is generating fundamental knowledge about the nature and behavior of living systems. Such knowledge is opening new possibilities to more precise ways of treating and preventing diseases all throughout the body, including those involving Kupffer cells and the liver.

References:

[1] Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, Ego KM, Bruni CM, Deng Z, Schlachetzki JCM, Nott A, Bennett H, Chang J, Vu BT, Pasillas MP, Link VM, Texari L, Heinz S, Thompson BM, McDonald JG, Geissmann F3, Glass CK. Immunity. 2019 Oct 15;51(4):655-670.

[2] Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Spengler EK, Loomba R. Mayo Clinic Proceedings. 2015;90(9):1233–1246.

Links:

Liver Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Nonalcoholic Fatty Liver Disease & NASH (NIDDK)

Glass Laboratory (University of California, San Diego)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Cancer Institute


Caught on Video: Cancer Cells in Act of Cannibalism

Posted on by

Tumors rely on a variety of tricks to grow, spread, and resist our best attempts to destroy them. Now comes word of yet another of cancer’s surprising stunts: when chemotherapy treatment hits hard, some cancer cells survive by cannibalizing other cancer cells.

Researchers recently caught this ghoulish behavior on video. In what, during this Halloween season, might look a little bit like The Blob, you can see a down-for-the-count breast cancer cell (green), treated earlier with the chemotherapy drug doxorubicin, gobbling up a neighboring cancer cell (red). The surviving cell delivers its meal to internal compartments called lysosomes, which digest it in a last-ditch effort to get some nourishment and keep going despite what should have been a lethal dose of a cancer drug.

Crystal Tonnessen-Murray, a postdoctoral researcher in the lab of James Jackson, Tulane University School of Medicine, New Orleans, captured these dramatic interactions using time-lapse and confocal microscopy. When Tonnessen-Murray saw the action, she almost couldn’t believe her eyes. Tumor cells eating tumor cells wasn’t something that she’d learned about in school.

As the NIH-funded team described in the Journal of Cell Biology, these chemotherapy-treated breast cancer cells were not only cannibalizing their neighbors, they were doing it with remarkable frequency [1]. But why?

A possible explanation is that some cancer cells resist chemotherapy by going dormant and not dividing. The new study suggests that while in this dormant state, cannibalism is one way that tumor cells can keep going.

The study also found that these acts of cancer cell cannibalism depend on genetic programs closely resembling those of immune cells called macrophages. These scavenging cells perform their important protective roles by gobbling up invading bacteria, viruses, and other infectious microbes. Drug-resistant breast cancer cells have apparently co-opted similar programs in response to chemotherapy but, in this case, to eat their own neighbors.

Tonnessen-Murray’s team confirmed that cannibalizing cancer cells have a survival advantage. The findings suggest that treatments designed to block the cells’ cannibalistic tendencies might hold promise as a new way to treat otherwise hard-to-treat cancers. That’s a possibility the researchers are now exploring, although they report that stopping the cells from this dramatic survival act remains difficult.

Reference:

[1] Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. Tonnessen-Murray CA, Frey WD, Rao SG, Shahbandi A, Ungerleider NA, Olayiwola JO, Murray LB, Vinson BT, Chrisey DB, Lord CJ, Jackson JG. J Cell Biol. 2019 Sep 17.

Links:

Breast Cancer (National Cancer Institute/NIH)

James Jackson (Tulane University School of Medicine, New Orleans)

NIH Support: National Institute of General Medical Sciences


Snapshots of Life: The Brain’s Microscopic Green Trash Bins

Posted on by

Zebrafish brain

Credit: Marina Venero Galanternik, Daniel Castranova, Tuyet Nguyen, and Brant M. Weinstein, NICHD, NIH

There are trash bins in our homes, on our streets, and even as a popular icon on our desktop computers. And as this colorful image shows, trash bins of the cellular variety are also important in the brain.

This image—a winner in the Federation of American Societies for Experimental Biology’s 2017 BioArt competition—shows the brain of an adult zebrafish, a popular organism for studying how the brain works. It captures dense networks of blood vessels (red) lining the outer surface of the brain. Next to many of these vessels sit previously little-studied cells called fluorescent granular perithelial cells (yellowish green). Researchers now believe these cells, often shortened to FGPs, act much like trash receptacles that continuously take in and store waste products to keep the brain tidy and functioning well.


Cool Videos: Spying on Cancer Cell Invasion

Posted on by

Spying on Cancer Cell Invation

If you’re a fan of the Mission: Impossible spy thrillers, you might think that secret agent Ethan Hunt has done it all. But here’s a potentially life-saving mission that his force has yet to undertake: spying on cancer cells. Never fear—some scientific sleuths already have!

So, have a look at this bio-action flick recently featured in the American Society for Cell Biology’s 2015 Celldance video series. Without giving too much of the plot away, let me just say that it involves cancer cells escaping from a breast tumor and spreading, or metastasizing, to other parts of the body. Along the way, those dastardly cancer cells take advantage of collagen fibers to make a tight-rope getaway and recruit key immune cells, called macrophages, to serve as double agents to aid and abet their diabolical spread.


Snapshots of Life: Host vs. Pathogen

Posted on by

Cryptoccocus neoformans

Caption: This scanning electron microscopy image shows mouse macrophages (green) interacting with a fungal cell (blue).
Credit: Sabriya Stukes and Hillary Guzik, Albert Einstein College of Medicine

Macrophages are white blood cells that generally destroy foreign invaders by engulfing them. It’s a tried-and-true strategy, but it doesn’t always work. Cryptoccocus neoformans, a deadly fungal pathogen commonly found in the feces of pigeons, can foil even the best macrophages. No one has captured this grand escape—but researchers are getting a whole lot closer to doing so.

Sabriya Stukes, an NIH-funded microbiologist at New York’s Albert Einstein College of Medicine, studies the interactions between C. neoformans and macrophages to determine how the former causes the lung infection cryptococcosis, which can be deadly for people with compromised immune systems. Stukes believes what makes C. neoformans so dangerous is that it can survive the acid death chamber inside macrophages—a situation that spells doom for most other pathogens. A big reason behind this fungus’s power of survival is its thick coat of polysaccharides, which serves as woolly-looking armor. Once a macrophage engulfs the fungus, this coat can give the white blood cell “indigestion,” prompting it to spit the fungus back into the lungs where it can cause disease.