The Potential Mechanisms Of Dendritic Cells-derived Interferon-λ1 Prevented Inflammatory Bone Destruction

BackgroundBone infection contributed to inflammatory osteolysis,which is common in orthopaedic surgery.The dynamic balance between bone formation and bone resorption was destroyed due to excessive osteoclast fusion and differentiation,resulting in the severe bone matrix loss.Many therapeutic approaches by restraining osteoclast formation and function acted as efficient ways to prevent inflammatory bone erosion.In this study,we have demonstrated for the first time that dendritic cells derived interferon-λ1(IFN-λ1)inhibited inflammatory bone destruction in vivo and explored its underlying mechanisms on osteoclast formation in vitro.Objectives1.To investigate the differentiated expression of IFN-λ1 between infectious bone tissue and non-infectious bone tissue.2.To explore the source of IFN-λ1 during bone infectious statement.3.To further investigate the effect and mechanism of exogeneous IFN-λ1 on osteoclastogenesis in vitro.4.To evaluate the effects of administration with IFN-λ1 on the inflammatory osteolysis mouse model in vivo.Methods1.The expression of IFN-λ1 between infectious bone tissue and non-infectious bone tissue was examined by using RNA-Seq method.2.The IFN-λ1 was derived from dendritic cells during the stimulation of LPS in inflammatory osteolysis,which was confirmed by using the co-culture between osteoclasts and LPS-stimulated dendritic cells.3.Also,the effects of IFN-λ1 on RANKL or LPS-induced osteoclast differentiation and bone resorption,and its impacts on RANKL-induced NF-κB p65 and NFATc1 nuclei translocation in vitro were detected.4.Moreover,the in vivo efficacy of IFN-λ1 by using LPS induced calvarial osteolysis mouse model was analyzed using micro-computed tomography(micro-CT),histology analysis and ELISA detection.Results1.IFN-λ1 was highly expressed in infectious bone tissue compared with noninfectious bone tissue.2.Dendritic cells were pre-treated with LPS showed that high expression of IFN-λ1.3.Moreover,the conditional medium of pre-treated with LPS on dendritic cells could significantly inhibit osteoclast differentiation through completing TRAP staining assay.Otherwise,this suppressive phenomenon could be reversed after adding IFN-λ1 monocloning antibody.4.It was also investigated that exogenous IFN-λ1 restrained osteoclastogenesis,bone resorptive activity,F-actin ring formation,osteoclast specific gene expression,the release of pro-inflammatory cytokines,p65 and NFATc1 translocation through preventing NF-κB signal pathway,NLRP3 inflammasome formation as well as inducing JAK-STAT signaling pathways in vitro.5.In vivo study indicated that IFN-λ1 prevents LPS-induced inflammatory bone destruction by inhibiting excessive osteoclast fusion and bone resorption activity.6.Taken together,our findings confirmed that dendritic cells derived IFN-λ1 could attenuate osteoclast formation and bone resorptive activity in vitro or in vivo.ConclusionIn summary,IFN-λ1 was more highly expressed in infectious tissue than in normal bone tissue,which contributed to activating inflammatory reactions.Moreover,the calvarial osteolysis model showed that treatment with IFN-λ1 dramatically prevented bone loss by regulating the inflammatory microenvironment.In addition,exogenous IFN-λ1 reversed the pathogenic process by regulating the release of pro-inflammatory cytokines.IFN-λ1 played an inhibitory role in osteoclast formation and function by directly inducing JAK-STAT signaling pathway.Generally,IFN-λ1 dramatically induced the activation of JAK-STAT signaling pathway so as to affect NF-κB p65 nuclear translocation,then inhibiting the release of pro-inflammatory cytokines and the formation of the NLRP3 inflammasome.As a result,IFN-λ1 served as a novel therapeutic target for the treatment of excessive osteoclast bone infectious diseases.