安徽医科大学,炎症新靶点 z-bio 2025-09-17 3090

　　Inflammation is the body's immune response to infection or damage, involving immune cells producing cytokines to activate downstream signaling pathways. Acute renal injury (AKI) is a condition of rapid renal decline, associated with renal and systemic inflammation, often caused by sepsis, toxins, or renal ischemia/reperfusion. Macrophages, as adaptive innate immune cells, play a key role in the inflammatory response. RNA modification, especially N7-methylguanosine (m7G), is known to play a role in a variety of biological processes, but its role in macrophages and inflammation is not yet known. This study aims to explore the role of METTL1-mediated m7G modification in macrophages and its function in inflammatory responses. A research team from Meng Xiaoming, Shen Yuxian and others of Anhui Medical University studied in-depth research on the role of METTL1-mediated m7G methylation in macrophages, especially in acute inflammation and multi-organ damage. Through a series of experiments, the article reveals the relationship between the upregulation of METTL1 expression in macrophages and the inflammatory response, and proposes the possibility of METTL1 as a potential therapeutic target. The relevant content was published in Science Immunology under the title "METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammation responses and multiple organ injury".

　　【主要内容】

　　Figure 1: Upregulation of METTL1 expression in monocytes/macrophages in AKI

　　Through immunofluorescence staining, METTL1 and CD68 (macrophage marker) were found to be co-localized in the kidney tissues of humans and mice. In mouse models, increased expression of METTL1 protein in renal tissues was observed, whether it was sepsis induced by cecum ligation perforation (CLP), renal ischemia/reperfusion (I/R), or cisplatin (CIS). In addition, flow cytometry analysis showed that METTL1 protein levels in Ly6Chi monocytes and MDMs were significantly increased in peripheral blood and renal tissues of AKI mice. In humans, the METTL1 protein levels of CD14+CD16−classical monocytes were also significantly upregulated in peripheral blood of AKI patients compared with healthy donors. These results suggest that METTL1 expression is upregulated in monocytes/macrophages in AKI, suggesting that it may be involved in the inflammatory response.

　　Figure 2: The loss of METTL1 in myeloid cells alleviates CLP-induced multi-organ damage and I/R-induced AKI

　　Figure 3: Deletion of METTL1 in myeloid cells inhibits the infiltration and differentiation of Ly6Chi macrophages

　　Figure 4: Transplantation of METTL1-deficient bone marrow relieves AKI in mice

Figure 5: Sarm1 mRNA is a target for METTL1-mediated m7G methylation

　　Through RNA sequencing and m7G methylation sequencing, it was found that after METTL1 knockdown, the m7G modification of Sarm1 mRNA decreased, and its mRNA and protein levels decreased on average. In addition, the m7G modification of Sarm1 mRNA is confirmed by methylated RNA immunoprecipitation (MeRIP)-qPCR experiments. In METTL1 knockout macrophages, the stability of Sarm1 mRNA is reduced, resulting in a decrease in its protein level. These results suggest that Sarm1 mRNA is a target for METTL1-mediated m7G modification, which enhances the stability of Sarm1 mRNA, and thus affects the inflammatory response of macrophages.

　　Figure 6: METTL1 promotes macrophage metabolic reprogramming through SARM1-mediated NAD+ depletion

　　The study found that METTL1-deleted macrophages showed higher NAD+/NADH ratio after LPS stimulation, indicating an increase in NAD+ levels. Furthermore, the oxygen consumption rate (OCR) of these macrophages increased, while the extracellular acidification rate (ECAR) decreased, indicating that metabolism shifted from glycolysis to oxidative phosphorylation. METTL1-deleted macrophages have decreased lactate levels, mitochondrial mass, increased mitochondrial membrane potential (MMP), and decreased reactive oxygen species (ROS) production. These results suggest that METTL1 promotes metabolic reprogramming of macrophages through SARM1-mediated NAD+ depletion, which in turn affects its inflammatory response.

　　Figure 7: Protective effect of METTL1 inhibitor SA91-0178 on CLP-induced multi-organ injury and I/R-induced AKI

　　In vitro experiments, SA91-0178 significantly inhibited the increase in m7G modification in LPS-induced macrophages and reduced the secretion of TNF-α and IL-1β. In vivo experiments, SA91-0178 pretreated mice had decreased serum Cre and BUN levels, decreased renal damage, decreased macrophage infiltration, and decreased SARM1 protein and mRNA levels after CLP or I/R induced damage. In addition, SA91-0178 administration 24 hours after injury also significantly alleviates multi-organ damage and reduces TNF-α levels. These results suggest that SA91-0178, as a METTL1 inhibitor, has a protective effect on acute inflammation and multi-organ injury.

　　【Full text summary】

　　This study revealed the relationship between the upregulation of METTL1 expression in macrophages and the inflammatory response through a series of experiments. The study found that METTL1 expression was significantly increased in acute renal injury (AKI) patients and mouse models, especially in Ly6Chi monocytes and MDMs. METTL1 knockout alleviates CLP-induced multi-organ inflammation and I/R-induced renal injury, reducing the production of inflammatory cytokines and infiltration of macrophages. Further mechanism studies have found that Sarm1 mRNA is a target of METTL1-mediated m7G modification. This modification enhances the stability of Sarm1 mRNA, leading to NAD+ imbalance, and thus affects the metabolic reprogramming of macrophages. In addition, the study also found that the specific METTL1 inhibitor SA91-0178, which is capable of alleviating inflammatory responses and tissue damage, showing potential as a potential drug for the treatment of acute inflammatory diseases. These findings provide a theoretical basis for the development of new therapies for systemic inflammation and multi-organ damage.