Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment
Cellular energy metabolism plays a crucial role in the regulation of macrophage polarization and in the execution of immune functions. A recent study showed that Slc6a8-mediated creatine uptake from exogenous supplementation modulates macrophage polarization, yet little is known about the role of th...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.937331/full |
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| author | Li Yu Lingwei Wang Guang Hu Laibin Ren Chen Qiu Shun Li Xiaohui Zhou Shanze Chen Rongchang Chen |
| author_facet | Li Yu Lingwei Wang Guang Hu Laibin Ren Chen Qiu Shun Li Xiaohui Zhou Shanze Chen Rongchang Chen |
| author_sort | Li Yu |
| collection | DOAJ |
| description | Cellular energy metabolism plays a crucial role in the regulation of macrophage polarization and in the execution of immune functions. A recent study showed that Slc6a8-mediated creatine uptake from exogenous supplementation modulates macrophage polarization, yet little is known about the role of the de novo creatine de novobiosynthesis pathway in macrophage polarization. Here, we observed that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, was upregulated in alternative (M2) polarized macrophages, and was dependent on the transcriptional factor STAT6, whereas GATM expression was suppressed in the classical polarized (M1) macrophage. Next, we revealed that exogenous creatine supplementation enhanced IL-4-induced M2 polarization, confirming recent work. Furthermore, we revealed that genetic ablation of GATM did not affect expression of M1 marker genes (Nos2, IL1b, IL12b) or the production of nitric oxide in both peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs). By contrast, expression levels of M2 markers (Arg1, Mrc1, Ccl17 and Retnla) were lower following GATM deletion. Moreover, we found that deletion of GATM in resident alveolar macrophages (AMs) significantly blocked M2 polarization but with no obvious effect on the number of cells in knockout mice. Lastly, an upregulation of GATM was found in lung tissue and bronchoalveolar lavage fluid macrophages from HDM-induced asthmatic mice. Our study uncovers a previously uncharacterized role for the de novo creatine biosynthesis enzyme GATM in M2 macrophage polarization, which may be involved in the pathogenesis of related inflammatory diseases such as an T helper 2 (Th2)-associated allergic asthma. |
| first_indexed | 2024-12-10T14:47:15Z |
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| language | English |
| last_indexed | 2024-12-10T14:47:15Z |
| publishDate | 2022-09-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-99a4bd6465864c75bc08df2e5bb594832022-12-22T01:44:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.937331937331Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatmentLi Yu0Lingwei Wang1Guang Hu2Laibin Ren3Chen Qiu4Shun Li5Xiaohui Zhou6Shanze Chen7Rongchang Chen8Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Animal Model, Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaDepartment of Animal Model, Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital (Shenzhen People’s Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, ChinaCellular energy metabolism plays a crucial role in the regulation of macrophage polarization and in the execution of immune functions. A recent study showed that Slc6a8-mediated creatine uptake from exogenous supplementation modulates macrophage polarization, yet little is known about the role of the de novo creatine de novobiosynthesis pathway in macrophage polarization. Here, we observed that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, was upregulated in alternative (M2) polarized macrophages, and was dependent on the transcriptional factor STAT6, whereas GATM expression was suppressed in the classical polarized (M1) macrophage. Next, we revealed that exogenous creatine supplementation enhanced IL-4-induced M2 polarization, confirming recent work. Furthermore, we revealed that genetic ablation of GATM did not affect expression of M1 marker genes (Nos2, IL1b, IL12b) or the production of nitric oxide in both peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs). By contrast, expression levels of M2 markers (Arg1, Mrc1, Ccl17 and Retnla) were lower following GATM deletion. Moreover, we found that deletion of GATM in resident alveolar macrophages (AMs) significantly blocked M2 polarization but with no obvious effect on the number of cells in knockout mice. Lastly, an upregulation of GATM was found in lung tissue and bronchoalveolar lavage fluid macrophages from HDM-induced asthmatic mice. Our study uncovers a previously uncharacterized role for the de novo creatine biosynthesis enzyme GATM in M2 macrophage polarization, which may be involved in the pathogenesis of related inflammatory diseases such as an T helper 2 (Th2)-associated allergic asthma.https://www.frontiersin.org/articles/10.3389/fimmu.2022.937331/fullmacrophagepolarizationcreatineglycine amidinotransferase (GATM)asthma |
| spellingShingle | Li Yu Lingwei Wang Guang Hu Laibin Ren Chen Qiu Shun Li Xiaohui Zhou Shanze Chen Rongchang Chen Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment Frontiers in Immunology macrophage polarization creatine glycine amidinotransferase (GATM) asthma |
| title | Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment |
| title_full | Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment |
| title_fullStr | Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment |
| title_full_unstemmed | Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment |
| title_short | Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment |
| title_sort | reprogramming alternative macrophage polarization by gatm mediated endogenous creatine synthesis a potential target for hdm induced asthma treatment |
| topic | macrophage polarization creatine glycine amidinotransferase (GATM) asthma |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.937331/full |
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