BackgroundMicroglia-mediated neuroinflammatory responses play important roles in secondary neurological injury after traumatic brain injury (TBI). The TGF-β pathway participates in the regulation of M1/M2 phenotype transformation of microglia. TGF-β can activate the Smad pathway by binding to TGF-βRs, which is regulated by the cleavage function of A disintegrin and metalloproteinase 17 (ADAM17). ADAM17, as an important regulatory factor of the TGF-β pathway, is considered an important factor in regulating the inflammatory response. However, the role of ADAM17 and the associated signaling pathways in the pathological process after TBI remain unclear.MethodsA rat model of TBI was established by the Feeney weight-drop method. Neurological severity, brain water content, and Nissl staining were used to evaluate the neuroprotective effect of inhibiting ADAM17 expression. In vitro and in vivo experiments were conducted to detect the transformation of microglia M1/M2 phenotype polarization and the neuroinflammatory response after specific inhibition of ADAM17. The formation of TGF-βRs and TGF-β1/TGF-βRII complexes on microglia were detected by immunofluorescence, western blot analysis, and co-immunoprecipitation in order to evaluate the effect of ADAM17 inhibition on the TGF-β1/Smad pathway. Meanwhile, Smad nuclear translocation, secretion, and TGF-β1/ Smad-mediated activation of the inflammatory reaction were referenced to evaluate the effects of ADAM17 inhibition and gain further insight into the mechanisms underlying development of the neuroendocrine response after TBI.ResultsADAM17 was highly expressed after TBI and mainly located in the microglia. Specific inhibition of ADAM17 reduced permeability of the blood-brain barrier, the degree of brain edema, and apoptosis of nerve cells, and improved neurological function after TBI. Further studies indicated that the neuroprotective effect of ADAM17 inhibition was related to a shift from the M1 microglial phenotype to the M2 microglial phenotype, thus reducing TBI-induced neuroinflammation. ADAM17 inhibition increased expression of TGF-βRs on the microglia membrane, promoted formation of TGF-β1/TGF-βRII complexes, and induced intranuclear translocation of Smads, which activated the TGF-β/Smad pathway. ADAM17 inhibition regulated microglia M1/M2 phenotype polarization through the TGF-β1/Smad pathway and influenced the neuroinflammatory response after TBI.ConclusionsMicroglial activation, the neuroinflammatory response, and the TGF-β1/Smad signaling pathway play essential roles in secondary injury after TBI. Specific inhibition of ADAM17 increased the expression of TGF-βRs on the microglia membrane and promoted formation of TGF-β1/TGF-βRII complexes. The TGF-β1/TGF-βRII complexes then induced intranuclear translocation of Smads, activated the TGF-β 1/Smad pathway, and regulated M1/M2 polarization of microglia, which influence the neuroinflammatory response as well as play a neuroprotective role after TBI

Glioma is a neural malignant tumor that resistant to radiotherapy and chemotherapy, for which surgery is a challenge due to the unclear boundary between glioma tissues and normal brain tissues. Radiofrequency ablation (RFA) is a substitute technology of surgery widely applied in the treatment of solid malignant tumors. However, recently researches indicate that the progression of hepatocellular carcinoma can be facilitated RFA. The present study aims to check whether the progression of glioma can be facilitated by RFA and investigate the underlying mechanism. The sublethal heat, which is regularly detected in the marginal zones of RFA treatments, was utilized to mimic the effects of RFA on glioma cells. Firstly, we found that the 50℃ was the optimized condition in U251 cells and SNB19 cells, which was verified by increased MTT absorbance, promoted invaded cells, accelerated cell cycle, increased clone formation, and faster growth rate in xenograft animals. Subsequently, P300 was found dramatically upregulated in 50℃ treated glioma cells, the progression of which was abolished by the knockdown of P300. Survival analysis revealed that longer survival was observed in P300 knockdown glioma cells. Furthermore, the expression level of β-catenin and its several target genes were positively correlated with P300. TGF-β promoter could be precipitated by the antibody of both P300 and β-catenin in P300-overexpressed glioma cells. Additionally, NF-κB p65 level in the nucleus was positively correlated with P300 and p-IκB was significantly upregulated under the stimulation of the sublethal heat treatment, while the effects of sublethal heat treatment on glioma cells were abolished by the mutation of IκB. P300 was identified to be regulated by NF-κB in a transcriptional level. Lastly, we found that P300 was upregulated in RFA treated patients and RFA induced a shorten overall survival. Collectively, our data implied that sublethal heat treatment facilitated the progression of glioma by recruiting the β-catenin pathway through regulating the NF-κB/P300 axis.