High-dose IL-37 promotes inflammatory activity of macrophage via Preferential ligation of the IL-18Rα

Interleukin-37 (IL-37) exists in various human tissues and organs and exhibits extensive anti-inflammatory activity. Recombinant IL-37 ameliorates the insulin resistance and inflammation associated with obesity and type 2 diabetes (T2DM). However, the specific role and underlying mechanisms of different doses of IL-37 in macrophage inflammatory response in T2DM remain to be discovered. In our study, we determined the dual role of IL-37 in macrophage inflammatory response both in vitro and vivo. We discovered that very low doses of IL-37 (10 ng/ml in vitro and 100 ng/ml in vivo) are sufficient to elicit significant anti-inflammatory effects. Conversely, high-dose IL-37 promotes the inflammatory response in macrophages. Specifically, a high dose of IL-37 (1000 ng/ml) did not improve blood glucose levels, intraperitoneal glucose tolerance, or insulin tolerance, nor did it reduce the number of islet macrophages in the T2DM model. Mechanistically, our in vitro and in vivo experiments demonstrated that high-dose IL-37 inhibited the activation of key signaling molecules such as phosphatase and tensin homolog (PTEN), AMP-activated protein kinase(AMPK), and signal transducer and activator of transcription 3 (STAT3) via preferential binding to IL-18Rα in macrophages. In contrast, low-dose IL-37 resulted in the activation of these signaling pathways. Collectively, these findings highlight low-dose IL-37 as a potential therapeutic agent to ameliorate inflammatory reactions and metabolic disturbances during T2DM. However, it is crucial to note that high-dose IL-37 may have no beneficial effects or could even exacerbate the condition.