FcγRIIb Exacerbates LPS-Induced Neuroinflammation by Binding with the Bridging Protein DAP12 and Promoting the Activation of PI3K/AKT Signaling Pathway in Microglia

Introduction: This paper focuses on the expression and role of Fc gamma RIIb in neuroinflammation, exploring the molecular mechanisms by which Fc gamma RIIb interacts with the bridging protein DAP12 to regulate the PI3K-AKT signaling pathway that promote neuroin-flammation and aggravate neuronal injury.Methods: LPS-induced neuroinflammation models in vivo and in vitro were constructed to explore the role and mechanism of Fc gamma RIIb in CNS inflammation. Subsequently, Fc gamma RIIb was knocked down or overexpressed to observe the activation of BV2 cell and the effect on PI3K-AKT pathway. Then the PI3K-AKT pathway was blocked to observe its effect on cell activation and Fc gamma RIIb expression. We analyzed the interaction between Fc gamma RIIb and DAP12 by Immunoprecipitation technique. Then Fc gamma RIIb was over-expressed while knocking down DAP12 to observe its effect on PI3K-AKT pathway. Finally, BV2 cell culture supernatant was co-cultured with neuronal cell HT22 to observe its effect on neuronal apoptosis and cell activity.Results: In vivo and in vitro, we found that Fc gamma RIIb expression was significantly increased and activated the PI3K-AKT pathway. Contrary to the results of overexpression of Fc gamma RIIb, knockdown of Fc gamma RIIb resulted in a significant low level of relevant inflammatory factors and suppressed the PI3K-AKT pathway. Furthermore, LPS stimulation induced an interaction between Fc gamma RIIb and DAP12. Knockdown of DAP12 suppressed inflammation and activation of the PI3K-AKT pathway in BV2 cells, and meantime overexpression of Fc gamma RIIb suppressed the level of Fc gamma RIIb-induced AKT phosphorylation. Additionally, knockdown of Fc gamma RIIb inhibited microglia activation, which induced neuronal apoptosis.Discussion: Altogether, our experiments indicate that Fc gamma RIIb interacts with DAP12 to promote microglia activation by activating the PI3K-AKT pathway while leading to neuronal apoptosis and exacerbating brain tissue injury, which may provide a new target for the treatment of inflammatory diseases in the central nervous system.