The involvement of endogenous melatonin in LPS-induced M1-like macrophages and its underlying synthesis mechanism regulated by IRF3

Melatonin (MLT) has been shown to induce polarization of macrophages towards M2-like phenotype and inhibit polarization of macrophages towards M1-like phenotype through exogenous administration, which affects the development of many macrophage polarization-related diseases, such as infectious diseases, cardiovascular diseases, bone diseases, and tumors. However, whether endogenous melatonin has similar influences on macrophage polarization as exogenous melatonin is still under investigation. This study revealed that the process of lipopolysaccharide (LPS) inducing macrophages to polarize towards M1-like phenotype was accompanied by an increase in endogenous MLT secretion. To explore the role of increased endogenous MLT in the polarization process of macrophages, whether similar to the function of exogenous MLT in inhibiting polarization of macrophages towards M1-like phenotype, we established LPS-induced MLT deficiency models in vitro to investigate the effects of endogenous MLT on the secretion of cytokines, co-stimulatory molecules, ROS, and phagocytic function in LPS-induced M1-like macrophages. Additionally, we aimed to elucidate the mechanism by which LPS affects the secretion of endogenous MLT by macrophages. Our results confirm that LPS induces transcription of Aanat through the TLR4/TRIF pathway, consequently facilitating the secretion of MLT by macrophages. In this way, IRF3 is the main transcription factor that regulates Aanat transcription. Endogenous MLT plays a role in inhibiting the polarization of macrophages towards M1 phenotype and delaying cell Apoptosis during LPS-induced polarization towards M1 phenotype. This phenomenon may be a form of self-protection that occurs when macrophages engulf pathogens while avoiding oxidative stress and Apoptosis caused by LPS. This conclusion clarifies the role of endogenous MLT in the clearance of pathogens by macrophages, providing a theoretical basis for understanding its role in innate immunity.

Aanat; Cell apoptosis; IRF3; Lipopolysaccharide; Macrophage polarization; Melatonin; Oxidative stress.