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

Abstract

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.

Lactobacillus paracasei L9 affects disease progression in experimental autoimmune neuritis by regulating intestinal flora structure and arginine metabolism

“…Macrophages are critical in the amplification and effector phase and damage the myelin sheath by phagocytic attack and release of inflammatory mediators such as toxic oxygen radicals, arachidonic acid metabolites, complement, or hydrolases [ 51 ]. Macrophage polarization is accompanied by dramatic changes in L-arginine metabolism [ 52 ]. The third metabolic fate of l -arginine is creatine generation, which acts as a key source of cellular energy reserve, yet little is known about the role of creatine in the immune system.…”

The Identification Distinct Antiviral Factors Regulated Influenza Pandemic H1N1 Infection

“…A previous study has shown that glycine amidinotransferase (GATM) was upregulated in M2-polarized macrophages. GATM deletion inhibited the expression of RETNAL and blocked M2 polarization [ 66 ]. Based on these, we speculate that GATM may regulate RETNLA to affect M2 macrophage polarization during H1N1pdms infection.…”

Integrative Analysis of Lactylome and Proteome of Hypertrophic Scar To Identify Pathways or Proteins Associated with Disease Development

“…GATM, the rate-limiting enzyme in creatine synthesis, was found to be upregulated in alternative (M2) polarized macrophages, and its expression was dependent on the transcriptional factor STAT6. Conversely, GATM expression was suppressed in classical polarized (M1) macrophages . Furthermore, GATM was observed to be upregulated in liver metastases, and it was discovered that creatine promotes cancer metastasis through the activation of Smad2/3 .…”

“…Conversely, GATM expression was suppressed in classical polarized (M1) macrophages. 60 Furthermore, GATM was observed to be upregulated in liver metastases, and it was discovered that creatine promotes cancer metastasis through the activation of Smad2/3. 61 Therefore, it is plausible that lactylation at K102 of GATM plays a role in the development of hypertrophic scars through the involvement of creatine and the Smad2/3 pathways.…”