Scientists discover new pathways controlling deadly inflammation

Inflammation is an important response to infection or injury, but needs to be carefully controlled as too much inflammation can cause conditions such as cancer, diabetes, heart disease and Alzheimer’s disease.

Research conducted at the MIMR-PHI Institute of Medical Research has provided new insights into how inflammation is controlled. In papers published in the prestigious journals Proceedings of the National Academy of Sciences USA and Nature Communications, the team led by Drs Tony Sadler and Dakang Xu, and Professor Bryan Williams (Sadler et al. PNAS, 2015; Sadler et al. Nature Commun, 2015) has discovered that a factor termed PLZF, originally identified to be involved in the development of a rare form of childhood leukaemia, plays a critical role in the important process of dampening inflammation to reduce it by restricting the expression of inflammatory gene products.

Previous research by the same team had identified PLZF protein as a host restriction factor limiting virus infection.

In these new studies, the team found that PLZF regulated the activity of protective cells called macrophages, controlling their ability to produce protein mediators of inflammation termed cytokines. When bacteria or viruses contact macrophages they are detected by specific receptors called Toll-like receptors. These receptors have evolved to become the first line of defence against viruses and bacteria. The team found that the triggering of Toll-like receptors by bacteria or bacterial or viral products instructs PLZF to dampen but not block the inflammatory response. In the absence of PLZF, higher levels of potent inflammatory cytokines are produced and there are exaggerated inflammatory responses to infections, which can be very dangerous.

In these papers the researchers have not only uncovered this novel role for PLZF, but have also identified the mechanisms by which PLZF is able to achieve its effects. It turns out that PLZF directly regulates the levels of cytokines being produced by controlling the expression of the genes responsible for producing these inflammatory proteins. In addition, the team has discovered the pathway that links the Toll-like receptors to PLZF and gene control.

Professor Williams, key researcher and Director of the MIMR-PHI Institute, said that drugs presently used to control inflammation are imprecise and either have significant side effects or work only in a select group of patients.

“By understanding the details of the regulatory processes that limit inflammation, we can begin to design more targeted therapeutic approaches,” said Professor Williams.

“These results also have significance for the application of the new immune therapy approaches showing promise in the treatment of different cancers. One of the side effects that needs to be monitored in these therapies is inflammation and consequently our results will also inform the use of immune therapy for cancer, in addition to providing targets for tackling other inflammatory conditions”.

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