Cell sub-issue: Jiang Peng's team from Tsinghua University reports that citrulline metabolism regulates macrophage inflammatory response

Macrophages are an important part of the body's anti-infection immune system, and 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), which is different from tumor cells
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The research team 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, Jiang Peng's group published a research paper entitled: Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses in the journal Molecular Cell
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The research team revealed the important role of the urea cycle metabolic enzyme ASS1 and its substrate citrulline in the innate immune response
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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 JAK2-STAT1 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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ASS1-mediated depletion of citrulline directly regulates macrophage pro-inflammatory activation and immune function Taken together, this work reveals the role of ASS1 in controlling inflammatory macrophage activation and antimicrobial defense by depleting cellular citrulline.
A central role to further identify citrulline as an innate immune signaling metabolite involved in a metabolic checkpoint of pro-inflammatory responses
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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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This project was funded by the Tsinghua-Peking University Life Joint Center and the National Natural Science Foundation of China
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Paper link: https:// Open for reprinting, welcome to forward to Moments and WeChat groups