The role of N-Glycan modification of TNFR1 in inflammatory microglia activation

Accumulating evidences demonstrated that microglia activation and the autocrine loop of tumor necrosis factor-alpha (TNF alpha) greatly contribute to the pathogenesis of several CNS diseases. TNF alpha exerts its biological effects by interacting with two different receptors: TNF receptor 1 (TNFR1) and TNFR2. The classic proinflammatory activity of TNF alpha is mainly mediated by TNFR1. In the present study, we found that TNFR1 was modificated by N-glycosylation on Asn151 and Asn202 in microglia. The N-glycosylation of TNFR1 could facilitate its capability of binding to TNF alpha and further promote the formation of TNF alpha autocrine loop in microglia stimulated by TNF alpha, resulting in excessive microglia activation and CNS inflammation. All these processes were related to TNFR1-mediated NF-kappa B pathways. Elimination of N-glycosylation did not affect the subcellular transportation and cell surface localization of TNFR1, but suppressed ligand-binding affinity. These findings indicated that the N-glycosylation of TNFR1 played an important role during microglia activation in CNS inflammation. By this study, we aimed to provide some valuable experimental evidence for a better understanding of the significance of protein glycosylation in microglia inflammatory activation and CNS disease.