Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment

Yu，Li1; Wang，Lingwei1; Hu，Guang1; Ren，Laibin1; Qiu，Chen1; Li，Shun2; Zhou，Xiaohui2; Chen，Shanze1; Chen，Rongchang1

2022-09-13

10.3389/fimmu.2022.937331

Frontiers in Immunology   Impact Factor & Quartile

1664-3224

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.

asthma creatine glycine amidinotransferase (GATM) macrophage polarization

SCI

English

First ; Corresponding

Sichuan Province Science and Technology Support Program[2019YFS0230];Natural Science Foundation of Guangdong Province[2022A1515011966];National Natural Science Foundation of China[81803183];National Natural Science Foundation of China[82170042];Shenzhen Science and Technology Innovation Program[JCYJ20210324114400002];

WOS:000861371300001

2-s2.0-85138985461

Scopus

1.Department of Pulmonary and Critical Care Medicine,The First Affiliated Hospital (Shenzhen People’s Hospital),School of Medicine,Southern University of Science and Technology,Shenzhen,China
2.Department of Animal Model,Shanghai Public Health Clinical Center,Fudan University,Shanghai,China

Yu，Li,Wang，Lingwei,Hu，Guang,et al. Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment[J]. Frontiers in Immunology,2022,13.

Yu，Li.,Wang，Lingwei.,Hu，Guang.,Ren，Laibin.,Qiu，Chen.,...&Chen，Rongchang.(2022).Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment.Frontiers in Immunology,13.

Yu，Li,et al."Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment".Frontiers in Immunology 13(2022).