Cytokine storm syndrome (CSS), characterized by severe systemic inflammation, is the leading cause of death in certain infectious diseases, such as Coronavirus disease 2019 and acute respiratory distress syndrome (Kim et al., 2021; Ramasamy and Subbian, 2021; Wang et al., 2020). Acute overwhelming inflammation caused by CSS is characterized by elevated levels of circulating cytokines and hyperactivation of immune cells, particularly macrophages (Grom et al., 2016). Macrophage hyperactivation markedly increases the levels of many pro-inflammatory cytokines, such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), thereby leading to a hyperinflammatory state associated with high mortality (Schulert and Grom, 2015). Macrophages are broadly classified into two categories according to their function: M1 (classical) and M2 (alternative). M1 triggers a rapid pro-inflammatory response to infection and tissue damage, whereas M2 exhibits anti-inflammatory and reparative activity, participating in inflammation remission and tissue repair (Covarrubias et al., 2015; Ginhoux et al., 2016; Murray et al., 2014). Therefore, targeting macrophages to achieve a precise balance of anti- and pro-inflammatory activity is a major avenue for the treatment of CSS. Currently, the main approach to treating CSS involves mitigating excessive immune responses through broad (e.g., glucocorticoid) and targeted (e.g., anti-cytokine) approaches (Schulert and Grom, 2014). However, those approaches elicit numerous adverse effects, such as hypertension and liver damage. Nutritional intervention is a relatively safe approach to alleviate CSS.

Macrophage polarization to M1 or M2 phenotypes has distinct metabolic requirements, in which the mechanistic target of rapamycin complex 1 (mTORC1) pathway plays a key role (Kang et al., 2018). mTORC1 is an important metabolic regulator that controls cell proliferation, differentiation, and immunity by sensing cellular energy status, nutrients, and external stimuli (Dibble et al., 2012). Amino acid restriction reprograms macrophage function through an mTOR-centric cascade (Orillion et al., 2018). Leucine, an important essential amino acid, is also a critical mTORC1 regulator (Jewell et al., 2015). The mTORC1 pathway plays a key role in controlling macrophage polarization (Byles et al., 2013). Recent studies have indicated that leucine blocks macrophage infiltration in obese animals, thus decreasing levels of the pro-inflammatory cytokine TNF-α and the macrophage marker F4/80⁺ in adipocytes (Macotela et al., 2011). However, the mechanism through which leucine alleviates inflammation is unclear.

In our study, we explored the effects of leucine on lipopolysaccharide (LPS)-induced CSS and elucidated the essential roles of leucine in CSS pathogenesis. We observed that leucine decreased mortality in mice treated with lethal doses of LPS. In addition, leucine decreased the expression and secretion of inflammatory factors in the serum and tissues of mice. In vitro data further confirmed that leucine inhibited LPS-driven M1 polarization and promoted M2 polarization through the mTORC1 signaling pathway, and leucine promoted M2 macrophage polarization through enhancing the expression of liver X receptor α (LXRα) induced by IL-4. Thus, our findings revealed a basic link between metabolism and immunity, in which leucine, via mTORC1/LXRα/Arg1, regulates the polarization of macrophages to M2 and alleviates inflammation.

CSS is an uncontrolled and immune dysregulated immune response involving the sustained activation and expansion of macrophages, which secrete large amounts of cytokines, these cytokines in turn lead to overwhelming systemic inflammation and multi-organ failure with high mortality (Chen et al., 2020; Copaescu et al., 2020). An imbalance between pro- and anti-inflammatory systems is the main cause of CSS, and macrophage polarization is important for maintaining immune homeostasis. M1 macrophages arise in inflammatory settings dominated by the interferon signaling associated with immunity to bacteria and intracellular pathogens, whereas M2 macrophages relieve inflammation and play important roles in fighting against and recovering from infection (Murray, 2017). Thus, therapeutic strategies that target macrophage polarization may be an approach to alleviate CSS.

In our study, leucine decreased LPS-induced inflammation and mortality. The uptake and metabolism of leucine regulated immune cell activation through the mTORC1 signaling pathway. Targeting leucine to manipulate immune responses have been suggested to be useful in the treatment of infections and autoimmunity (Ananieva et al., 2016). A previous study has found that leucine inhibits the expression of inflammatory factors in LPS-stimulated RAW 264.7 cells, but the specific mechanism has not been clarified (Lee et al., 2017). Our research further verified that leucine alleviates inflammation by inhibiting LPS-stimulated M1 polarization and promoting M2 polarization in both animals and BMDMs.

Macrophage polarization is critical for immune homeostasis. In our study, leucine not only decreased the LPS-mediated production of pro-inflammatory factors such as IL-6, IFN-γ, and TNF-α, but also promoted the expression of the M2 macrophage markers Mgl1 and Mgl2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are sensitive indicators of liver damage. LPS led to significant increase in AST and ALT in both serum and liver, whereas leucine decreased AST and ALT levels, indicating that leucine mitigated tissue damage (Figure 5—figure supplement 2A). Importantly, leucine significantly inhibited the high mortality caused by LPS. Therefore, we hypothesized that leucine might regulate macrophage polarization in LPS-induced CSS. Indeed, leucine has been found to directly promote M2 macrophage polarization in vitro, because the addition of leucine markedly increases the expression of M2-associated genes in IL-4-stimulated BMDMs, as well as arginase-1 activity, which is crucial for M2 macrophage polarization (Zhang et al., 2020a). Moreover, leucine alone did not increase the expression of M2-associated genes in BMDMs, thus further indicating that leucine synergistically enhances IL-4-induced gene expression and subsequent M2 polarization. CSS is caused by a severe pro-/anti-inflammatory imbalance of macrophages, in which M2, which plays important roles in inflammation relief and tissue repair, is diminished (Cosín-Roger et al., 2016). Herein, we demonstrated that leucine alleviates inflammation in LPS-induced CSS, possibly through its ability to promote M2 polarization.

mTORC1 is known to integrate information about cellular nutritional status, including amino acid levels, thus altering cell signaling through a wide range of downstream targets (Wolfson and Sabatini, 2017). Recent studies have revealed the crucial importance of the mTORC1 pathway in controlling macrophage polarization, and the strong connections among the regulation of macrophage activity, nutrition sensing, and metabolic status (Papathanassiu et al., 2017Byles et al., 2013; Kobayashi et al., 2021). Nutrient status, particularly that of amino acids, regulates macrophage polarization via mTORC1 remains unclear. Among amino acids, leucine is a potent activator of mTORC1 in macrophages (Zhang et al., 2020b). Leucine activates mTORC1 primarily by blocking the inhibitory effect of the protein setrin2 on the GATOR2, a complex that activates mTORC1 (Wolfson et al., 2016). Recently, leucine has been found induce mTORC1 activation in macrophages, thus further regulating macrophage polarization (Li et al., 2019).

However, the specific mechanism through which leucine regulates macrophage polarization has not been reported. Akt–mTORC1 signaling integrates metabolic inputs to control macrophage activation. Wortmannin inhibition of AKT was followed by inhibition of M2 polarization, suggesting that AKT signaling is involved in M2 polarization (Figure 3—figure supplement 1B). Studies reported that mTORC1 activation inhibits pAkt (T308), inhibition of mTORC1 in turn activate Akt (Byles et al., 2013), promoting M2 polarization as a feed back to compensate the inhibition of mTORC1-induced suppression of M2 polarization. mTORC2, directly phosphrlate Akt at S473, and inhibition of mTORC2 inhibits p-Akt (S473) (Leontieva et al., 2014), further inhibiting M2 porlarization. Torin1 is the inhibitor for both, while rapamycin is specially for mTORC1 (Zhao et al., 2015). In this study, torin significantly decreased p-Akt (S473), and thus additionally inhibits mTORC2 showing a better inhibition of M2 than rapamycin (Figure 3—figure supplement 1C).

In M2 macrophages, Arg1 plays a pivotal role in a hallmark characteristic by catalyzing the hydrolysis of L-arginine into L-proline and polyamines, which subsequently downregulate the transcription of pro-inflammatory cytokine TNF-α in macrophages, thereby attenuating local inflammation and promoting tissue repair. Our research findings demonstrate that inhibiting mTORC1 significantly reduces Arg1 expression. Macrophage polarization is regulated by various transcription factors, among which STAT6 is indispensable for M2 polarization. Stimulation of macrophages with IL-4 leads to IL-4R signaling and phosphorylation of the transcription factor STAT6 at tyrosine residues, facilitating its nuclear translocation and induction of target genes. Studies have shown that STAT6/Arg1 is an important signaling mechanism in macrophage phenotypic regulation (Cai et al., 2019).Therefore, we hypothesized that leucine might regulate M2 polarization through the mTORC1/STAT6/Arg1 pathway. Indeed, after IL-4 stimulation, STAT6 was tyrosine phosphorylated, but inhibition of mTORC1 did not alter the expression of STAT6. Moreover, leucine increased STAT6 phosphorylation in IL-4-stimulated BMDMs, but leucine alone did not activate STAT6. These findings indicated that leucine promotes macrophage M2 polarization independently of the mTORC1/STAT6/Arg1 pathway.

Beyond STAT6, a prior study has identified that LXRα regulates Arg1 expression in macrophages by promoting binding of the hematopoietic transcription factors IRF8 and PU.1 to the transcription start site in the Arg1 gene. The importance of LXRα in inhibiting the expression of inflammatory mediators in macrophages and macrophage differentiation has been reported (A-Gonzalez et al., 2013; Joseph et al., 2003). LXRα knockout decreases Arg1 expression, thus enhancing inflammation signatures of macrophages and ultimately inhibiting recovery after injury (Mao et al., 2021). However, whether leucine regulates M2 polarization through mTORC1/LXRα must be verified. After inhibition of mTORC1, the protein expression of LXRα decreased, and Arg1 expression was also significantly inhibited. Moreover, after LXRα inhibition, the expression of Arg1 decreased significantly, thereby confirming that active LXRα is necessary for M2 polarization. These findings indicated that leucine-mediated M2 polarization may occur via the mTORC1/LXRα/Arg1 pathway. Indeed, we extracted macrophage nuclear proteins and found that leucine effectively promoted LXRα entry into the nucleus. Thus, our results showed that mTORC1 integrates intracellular leucine signaling and external IL-4 signaling, thus activating its downstream transduction factor LXRα, and promoting LXRα entry into the nucleus and the induction of the target gene Arg1, and ultimately leading to M2 polarization.

Our results suggested that leucine regulates M2 via the mTORC1/LXRα/Arg1 pathway, thus alleviating LPS-mediated CSS. Leucine also has regulatory effects on M1. In present study, we report the first evidence that leucine decreases mortality in mice after a lethal dose of LPS, and attenuates secretion of the pro-inflammatory factors IL-6, IFN-γ, and TNF-α in the serum. The anti-inflammatory effects of leucine were probably mediated by modulation of macrophage polarization, because leucine suppressed CD86 expression (M1 macrophage marker) but increased CD206 (M1 macrophage marker) expression in both the bone marrow and spleen. This possibility was corroborated by in vitro data in BMDMs. Leucine inhibited LPS-driven M1 polarization, and decreased the secretion of IL-6, IL-1β, and TNF-α in BMDMs. Together, our in vivo and in vitro results suggest that leucine may also inhibit inflammation driven by M1 macrophages. Therefore, subsequent studies of the specific mode of action of leucine on the polarization of M1 macrophages will be essential.

Conclusions

In summary, the present study revealed that leucine ameliorates CSS in mice exposed to LPS by inhibiting macrophage M1 polarization and promoting M2 polarization. On the basis of our results, a role of leucine in macrophage inflammatory responses via the mTORC1/LXRα/Arg1 axis is proposed (Figure 6), in which leucine promotes M2 macrophage polarization through the mTORC1/LXRα/Arg1 signaling pathway, thereby contributing to the resolution of inflammation and the repair of damaged tissues.

Figure 6

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Author details

1. Hui Yan

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Conceptualization, Resources

   Contributed equally with

   Yao Liu and Xipeng Li

   For correspondence

   yan.hui@sicau.edu.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7476-3914

2. Yao Liu

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Conceptualization, Data curation, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Contributed equally with

   Hui Yan and Xipeng Li

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5141-3161

3. Xipeng Li

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Writing – original draft

   Contributed equally with

   Hui Yan and Yao Liu

   Competing interests

   No competing interests declared

4. Bing Yu

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

5. Jun He

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Visualization

   Competing interests

   No competing interests declared

6. Xiangbing Mao

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Jie Yu

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Project administration

   Competing interests

   No competing interests declared

8. Zhiqing Huang

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5092-9297

9. Yuheng Luo

   Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

   Contribution

   Visualization

   Competing interests

   No competing interests declared

10. Junqiu Luo

    Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

    Contribution

    Methodology

    Competing interests

    No competing interests declared

11. Aimin Wu

    Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

    Contribution

    Writing – review and editing

    Competing interests

    No competing interests declared

12. Daiwen Chen

    Key Laboratory of Animal Disease Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease resistant Nutrition of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China

    Contribution

    Resources, Methodology, Writing – original draft, Writing – review and editing

    For correspondence

    dwchen@sicau.edu.cn

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8351-7421

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