Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2

Clocking in on the immune response

28 February 2019

An antioxidant that has been linked to the benefits of blueberries could help reduce excessive inflammation at night

Suppressing the immune response at specific times of the day could reduce inflammation caused by illness or injury.

Most living things, from fish to fungi, have an internal biological clock synced with the 24-hour night–day cycle. This clock anticipates changes in the environment and triggers appropriate responses.

In humans, these molecular clocks drive bodily functions such as sleep and digestion. But such rhythmicity has also been observed in the inflammatory response to diseases such as arthritis and multiple sclerosis. Since excessive inflammation can hinder the recovery of damaged tissues, it could be beneficial to suppress this overzealous immune response.

The body’s core molecular clock protein, BMAL1, has been linked to the inflammatory response of numerous conditions, but its precise function has not been fully explored.

Annie Curtis of the Royal College of Surgeons in Ireland and her team are getting closer to completing the picture. “In chronic inflammatory diseases, macrophages — immune cells that provide the first line of defence — go into overdrive, producing excessive amounts of a molecule called IL-1β that triggers inflammation,” explains Curtis. “So we decided to investigate if and how the biological clock controls the response of macrophages.”

Curtis and her team bred mice both with and without the BMAL1 protein in their macrophages, and stimulated these cells with lipopolysaccharide, a bacterial toxin that mimics an inflammatory response.

The researchers then extracted the affected macrophages from the mice at intervals throughout the day. They found that the cells lacking BMAL1 produced much more IL-1β than the cells with normal levels of BMAL1.

“We analysed many molecules that could drive this behaviour and were glad to find that just one, the NRF2 protein, was responsible.” NRF2 — an antioxidant that is activated by blueberry extracts — limits inflammation by blocking the release of IL-1β from the immune cells.

The researchers noticed a peak in the activities of both BMAL1 and NRF2 proteins in the mouse macrophages 8 hours after lights out in the lab, and a corresponding trough around 8 hours after lights on.

This connection could help explain why shift workers with disrupted sleep patterns are more prone to inflammatory conditions and hence provide a basis for determining the best time of day to treat them.

“We don’t know why, but humans experience most inflammation at night,” says Curtis, “so boosting NRF2 levels during the night could help limit that inflammation.”

The team next hopes to figure out exactly how BMAL1 controls NRF2. “A full understanding of the mechanisms involved should help us target them more intelligently,” notes Curtis.

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References

1. PNAS 115, E8460–E8468 (2018). doi: 10.1073/pnas.1800431115