Fc[gamma]Rllb Exacerbates LPS-lnduced Neuroinflammation by Binding with the Bridging Protein DAP 12 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 neuroinflammation 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. Keywords: LPS-induced neuroinflammation, Fc[gamma]RIIb, DAP12, microglia, PI3K-AKT