Downregulation of the O-GlcNAc signaling promotes activation of the innate immune response in microbial sepsis

Abstract

Abstract Sepsis is the most common cause of death in intensive care units. Acute systemic inflammatory responses mediate morbidity in microbial sepsis. Studies of immune system metabolism have recently identified the tight link between metabolic reprogramming and immune system activation. A robust increase in glucose metabolism is observed in the initial phase of sepsis, indicating the involvement of glucose metabolism in the pathogenesis of sepsis. However, the role of individual glucose metabolism pathways in the regulation of septic inflammation is poorly understood. The hexosamine synthesis pathway (HBP) is a unique glucose metabolism pathway leading to protein modification by the O-linked b-N-acetylglucosamine (O-GlcNAc), a process known as O-GlcNAcylation. Here we report a critical role of HBP-associated O-GlcNAc signaling in modulating septic inflammation. Activation of TLR4 signaling results in decreased HBP flux activity and protein O-GlcNAcylation in macrophages. Decreased O-GlcNAc signaling is also observed in peritoneal macrophages following cecal ligation and puncture (CLP)-induced experimental sepsis, indicating that decreased O-GlcNAc signaling may exacerbate septic inflammation. Myeloid-specific deletion (OgtΔmye) of O-GlcNAc transferase (OGT), the key enzyme mediating protein O-GlcNAcylation, leads to increased activation of the NF-κB signaling and cytokine production upon the stimulation with various TLR agonists. Furthermore, OgtΔmye mice show increased susceptibility to LPS-induced endotoxin shock and CLP-induced sepsis. These findings identify a novel link between glucose metabolism and innate immune activation and suggest OGT as a therapeutic target for treating microbial sepsis.