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

Aug 22, 2018Proceedings of the National Academy of Sciences of the United States of America

The body’s internal clock protein BMAL1 controls inflammation in immune cells through NRF2

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Abstract

Deletion of the core molecular clock protein resulted in increased production of the proinflammatory cytokine IL-1β.

Innate immune responses are influenced by the time of day, and disruptions in molecular clocks can affect inflammation.
is essential for controlling inflammation by suppressing reactive oxygen species and proinflammatory cytokines.
Loss of BMAL1 decreases NRF2 response to LPS challenge, leading to reduced antioxidant activity and glutathione synthesis.
Increased levels of reactive oxygen species and HIF-1α were observed in macrophages lacking BMAL1.
Activation of NRF2 or addition of antioxidants can mitigate the excessive inflammatory response in BMAL1-deficient macrophages.

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A variety of innate immune responses and functions are dependent on time of day, and many inflammatory conditions are associated with dysfunctional molecular clocks within immune cells. However, the functional importance of these innate immune clocks has yet to be fully characterized. plays a critical role in the innate immune system, limiting inflammation via reactive oxygen species (ROS) suppression and direct repression of the proinflammatory cytokines, IL-1β and IL-6. Here we reveal that the core molecular clock protein, , controls the mRNA expression ofvia direct E-box binding to its promoter to regulate its activity. Deletion ofdecreased the response of NRF2 to LPS challenge, resulting in a blunted antioxidant response and reduced synthesis of glutathione. ROS accumulation was increased inmacrophages, facilitating accumulation of the hypoxic response protein, HIF-1α. Increased ROS and HIF-1α levels, as well as decreased activity of NRF2 in cells lacking BMAL1, resulted in increased production of the proinflammatory cytokine, IL-1β. The excessive prooxidant and proinflammatory phenotype ofmacrophages was rescued by genetic and pharmacological activation of NRF2, or through addition of antioxidants. Our findings uncover a clear role for the molecular clock in regulating NRF2 in innate immune cells to control the inflammatory response. These findings provide insights into the pathology of inflammatory conditions, in which the molecular clock, oxidative stress, and IL-1β are known to play a role. Nrf2Bmal1Bmal1Bmal1 -/--/-

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

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