Choline is necessary for the macrophage inflammatory response

Author : Shannon Cox. Curtis Clock Lab, Royal College of Surgeons in Ireland.

Highlighted Article : Choline uptake and metabolism modulate macrophage IL-1β and IL-18 production

Elsa Sanchez-Lopez, Zhenyu Zhong, Alexandra Stubelius, Shannon R. Sweeney, Laela M. Booshehri, Laura Antonucci, Ru Liu-Bryan, Alessia Lodi, Robert Terkeltaub, Juan Carlos Lacal, Anne N. Murphy, Hal M. Hoffman, Stefano Tiziani, Monica Guma, and Michael Karin

DOI: 10.1016/j.cmet.2019.03.011

Cell Metab. 2019 Apr 8. pii: S1550-4131(19)30139-1

Choline is an essential nutrient required for the structural integrity of cells in our body, including immune cells like macrophages.  In cancer and inflammatory diseases, uptake of choline by cells is used as an indicator of enhanced cell proliferation. Macrophages take up choline at sites of inflammation, however the effect of enhanced choline uptake on macrophage driven inflammation is unknown. In this study, the authors investigated how inhibition of choline uptake affected the inflammatory responses from macrophages.

Macrophages upon encountering a pathogen or damage produce pro-inflammatory proteins such as IL-1β and IL-18. The authors mimicked this response by exposing macrophages to bacterial lipopolysaccharide (LPS), a component of gram negative bacteria. LPS sensing by macrophages leads to the activation of a number of protein complexes required for the production of IL-1β and IL-18. Sanchez-Lopez et al. revealed that LPS treatment led to choline uptake via its transporter CTL1, while a lack of choline or CTL1 led to a decrease in IL-1β through inhibition of the NLRP3 inflammasome, a protein complex required for IL-1β production. The authors also found that choline deficiency in macrophages led to low energy in cells, and this low energy state suppressed IL-1β production and therefore reduced inflammation.

In mice, blocking choline using an inhibitor reduced IL-1β and thus inflammation, providing protection from lethal septic shock. A family of genetic conditions known as cryopyrin-associated periodic syndromes (CAPS)  are associated with constant IL-1β production. Blocking choline also reduced IL-1β in mouse models of these conditions.

In addition to CAPs, dysregulated inflammation is the basis of a number of chronic conditions including diabetes, Alzheimer’s disease, and arthritis and also the life threatening condition sepsis . Understanding the control pathways of inflammation in key inflammatory immune cells like macrophages opens up new pathways for therapeutic manipulation. Therefore choline inhibitors may be useful in treating a number of inflammatory type conditions.

Figure 1:  Inhibition of choline uptake leads to reduction in macrophage inflammatory responses. Source:  https://www.sciencedirect.com/science/article/pii/S1550413119301391?via%3Dihub

Figure 1: Inhibition of choline uptake leads to reduction in macrophage inflammatory responses. Source: https://www.sciencedirect.com/science/article/pii/S1550413119301391?via%3Dihub

Loss of the macrophage circadian clock contributes to diversity in the inflammatory response

Author : James O’Siorain. Curtis Clock Lab, Royal College of Surgeons in Ireland.

Reviewed Article: Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response.

Nancy C. Allen, Naomi H. Philip, Lucy Hui, Xu Zhou, Ruth A. Franklin, Yong Kong and Ruslan Medzhitov

DOI: 10.1126/scisignal.aau1851

Sci. Signal. 12 (571), eaau1851.

Many cells including immune cells such as macrophages exhibit a wide variety of responses to the same stimulus, even though we expect them to respond identically. As researchers we often call these different responses “background noise”. In the body, systemic time-rhythmic signals like cortisol synchronise cells, through their 24-hour molecular clock or circadian clock. However no systemic signals exist in culture, and as such circadian rhythmicity is lost. In this study, the authors investigated if this loss of circadian rhythmicity in culture may be contributing to background noise.

A frequent technique in immunology research is to treat macrophages with the bacterial component lipopolysaccharide (LPS), mimicking their response to a bacterial infection. Allen et al. isolated macrophages from mouse peritoneum at different times of day, stimulated with LPS, then used flow cytometry to see how the response changes across the whole population. They found that macrophages variably produce the inflammatory protein IL-12p40. Subsequent analysis demonstrated that IL-12p40 production was dependent on the clock-controlled genes, Nfil3 and Dbp. These genes have opposing effects on IL-12p40, with Nfil3 reducing, and Dbp enhancing the production of IL-12p40. While most macrophages readily produce IL-12p40, the production in others is hugely dependent on clock-time, while a further subset never produce IL-12p40.

These results are fascinating because they describe a threshold-of-activation for IL-12p40 production that is partially dependent on clock-timing.   This reaffirms our understanding for the need of a balanced immune response and how disruption of our body clocks affects this balance. This study describes that  the variability (or background noise) in macrophage responses to LPS, is partially dependent on NFIL3 and DBP abundance within each cell. However, there are many more ways by which the clock controls the inflammatory response. Circadian control over processes such as cell signaling, metabolism, and protein and nucleic acid modifications, likely contribute further to the heterogynous responses of the macrophage.

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