October 1, 2013

Immune System Research Linked to Obesity

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According to the Center for Disease Control, more than one in every three American adults is obese. Obese individuals are at a greater risk for cancer and other diseases, but the reason for this association has never been determined.

Prof. Scott Coonrod, reproductive biology, and Sunish Mohanan grad are studying the reason for this increased risk.

“Genetics and pathways in cancer cells have been studied for several decades, and we are still not close to understanding the complex factors in determining malignancy,” Mohanan said.

With this in mind, Coonrod’s lab has been looking at cancer from a new angle, focusing on the microenvironment that the cancer cells are living in rather than the inner workings of the cells themselves. According to Monahan, the lab is focusing on how the inflammatory environment around dying fat tissue in obese individuals is modified when the fat tissue is infiltrated with clusters of macrophages.

Macrophages are immune system cells that, under normal conditions, fight against disease by engulfing bacteria and other pathogens as well as infected cells.

Other immune cells fight diseases and injury by forming traps outside the cell. When the body is wounded, such immune cells arrive at the site of injury and expel their DNA to form this extracellular structure, according to Coonrod.

The DNA is sticky, allowing it to clean up bacteria and keep the site free of infection.

In obese individuals, pockets of inflammation and dying fat tissue are more prevalent due to an insufficient amount of blood supply to some areas of the body. Coonrod and Mohanan discovered that macrophages also release extracellular traps around these areas of inflammation.

Three meters of cellular DNA is kept inside the nucleus of each macrophage. This negatively charged DNA is wound around positively charged protein balls called histones. A group of enzymes called peptidylarginine deiminases are able to remove the positive charge from the histone proteins and break the attraction between DNA and the histone, according to Coonrod. When there is no longer an attraction to keep the DNA on the histone, the DNA is released into the space outside the cell.

This process of neutralizing the histone, known as citrullination, is only seen in diseased tissue. The environment in healthy tissue prevents citrullination while the environment in diseased tissue facilitates this process.

Although PAD enzymes are present in all macrophages, it is only when problems occur that the histone proteins are altered and the DNA is released. DNA expulsion is one of the last steps before the macrophage dies. According to Coonrod, upon death, the macrophage releases factors to attract more macrophages to the area. This process allows macrophages to accumulate quickly in diseased tissue.

“What we really want to know is what is in the environment of the diseased tissue that’s signaling to the PAD enzymes in the macrophage, causing them to be activated,” Coonrod said.

According to Coonrod, the next step for the lab’s research is to learn exactly what factors are released by the dying macrophages which attract more immune cells to diseased sites.

In the future, Coonrod will also look into how these discoveries may translate into medical or pharmaceutical solutions to various diseases.

Prof. Paul Thompson, Scripps Research Institute, one of Coonrod’s collaborators, has already developed a set of drugs that attaches to the PAD enzymes and stops their activity. These drugs have been used by the Coonrod Lab to block cancer growth and suppress trap production.

“There is a huge area of medicine that has yet to be tapped,” Coonrod said. “If you could somehow prevent these [macrophage] traps from occurring, you might be able to resolve different diseases.”