ADAM17&nbsp;Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway Following Experimental Traumatic Brain Injury
Authors: chen xiangrong , Zeng Yile , Wang Fan , Yao Jieran , Lv Wenqi , Ding Chenyu , Tu Xiankun 
Published: February 2021

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