Mol Cell Jiang Peng's research group reports that citrulline metabolism regulates the inflammatory response of macrophages

Editor-in-Chief | Xi Macrophages are an important part of the body's anti-infection immune system
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The immune function of macrophages is affected by changes in intracellular and extracellular metabolites
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Arginine metabolism has long been recognized as an important metabolic regulator regulating macrophage polarization and inflammatory responses
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In the body, arginine is one of the intermediate metabolites in the metabolic pathway of the urea cycle
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A recent study by Jiang Peng's group at the School of Life Sciences, Tsinghua University revealed that abnormal changes in the urea cycle significantly affect the ammonia metabolism and polyamine biosynthesis of tumor cells (Li et al.
2019, Nature) (Expert Comments Nature | Tsinghua University) Jiang Peng group revealed the molecular mechanism and function of abnormal ammonia metabolism in tumors)
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Unlike tumor cells, the researchers found that the expression of CPS1 in bone marrow-derived macrophages was extremely weak, implying that the urea cycle may have different metabolic mechanisms and functions in macrophages
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On January 10, 2022, the research group published an article titled "Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses in the journal Molecular Cell.
necessary for cellular activation and immune responses)" research paper
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In this work, the researchers revealed the important role of the urea cycle metabolizing enzyme ASS1 and its product citrulline in innate immune responses
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Induction of pro-inflammatory polarization in mouse bone marrow-derived macrophages resulted in a marked increase in the expression of ASS1, which was accompanied by the depletion of its metabolic substrate citrulline and the depletion of other metabolites in the urea cycle.
levels did not change significantly
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In-depth mechanism exploration found that during the pro-inflammatory polarization of macrophages, the activation of the JAK-STAT signaling pathway up-regulated the transcriptional expression of ASS1, and at the same time rapidly phosphorylated the Y87 site of ASS1 in a short period of time, thereby increasing ASS1.
enzymatic activity and lead to rapid and violent depletion of intracellular citrulline
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A more in-depth study found that knockdown of ASS1 leads to the accumulation of citrulline in macrophages, and high levels of citrulline directly bind to JAK2, thereby weakening the binding of JAK2 to IFNγR2 and STAT1, and inhibiting JAK2-STAT1 signaling pathway activity, thereby inhibiting the pro-inflammatory polarization of macrophages and the ability of mice to resist infection
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Taken together, this work reveals a central role for ASS1 in controlling inflammatory macrophage activation and antimicrobial defense by depleting cellular citrulline, and further identifies citrulline as an innate immune signaling metabolite involved in pro-inflammation.
Metabolic checkpoints for reactions
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 Figure 1.
ASS1-mediated depletion of citrulline directly regulates pro-inflammatory activation and immune function in macrophages
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 Mao Youxiang, a 2016 doctoral student at the School of Life Sciences of Tsinghua University, is the first author of the paper, and Jiang Peng, a researcher at the School of Life Sciences and the Joint Center for Life Sciences of Tsinghua University, is the corresponding author of the paper
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Link to the original text: https://doi.
org/10.
1016/j.
molcel.
2021.
12.
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, Du, W.
, Yu, L.
, and Jiang, P.
( 2019).
p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis.
Nature 567, 253–256.