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Updated: Aug 3, 2025
Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway
Xiangrong Chen1,2,3,4, Jieran Yao4,5, Jinqing Lai4
1Department of Neurosurgery, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China.
Abstract:
Microglia-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). However, the role of ADAM17 and the associated signaling pathways in the pathological process after TBI remain unclear. Herein, we assessed the transformation of microglia M1/M2 phenotype polarization and the neuroinflammatory response after the inhibition of ADAM17. The formation of TGF-βRs and TGF-β1/TGF-βRII complexes on microglia were detected to evaluate the effect of ADAM17 inhibition on the TGF-β1/Smad pathway. ADAM17 was highly expressed after TBI and mainly located in the microglia. the inhibition of ADAM17 improved neurological function after TBI. 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. In conclusion, our study suggested that ADAM17 inhibition regulated microglia M1/M2 phenotype polarization through the TGF-β1/Smad pathway and influenced the neuroinflammatory response after TBI.
Insights
Inhibiting ADAM17 after traumatic brain injury (TBI) improves neurological function by shifting microglia from M1 to M2 phenotypes, reducing neuroinflammation via the TGF-β/Smad pathway.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia-driven neuroinflammation is critical in secondary injury following traumatic brain injury (TBI).
- The transforming growth factor-beta (TGF-β) pathway influences microglial M1/M2 polarization.
- A disintegrin and metalloproteinase 17 (ADAM17) regulates TGF-β activation, but its role in TBI is unknown.
Purpose of the Study:
- To investigate the role of ADAM17 in TBI pathophysiology.
- To assess the impact of ADAM17 inhibition on microglial polarization and neuroinflammation post-TBI.
Main Methods:
- Assessed microglial M1/M2 phenotype polarization and neuroinflammation after ADAM17 inhibition in a TBI model.
- Detected TGF-β receptor (TGF-βR) formation and TGF-β1/TGF-βRII complex assembly on microglia.
- Evaluated the effect of ADAM17 inhibition on the TGF-β1/Smad signaling pathway.
Main Results:
- ADAM17 expression was elevated post-TBI, primarily in microglia.
- ADAM17 inhibition improved neurological function and reduced neuroinflammation.
- Inhibition shifted microglia from M1 to M2 phenotypes, increasing TGF-βRs and Smad activation.
Conclusions:
- ADAM17 inhibition confers neuroprotection after TBI.
- This effect is mediated by regulating microglial M1/M2 polarization through the TGF-β1/Smad pathway.
- ADAM17 is a potential therapeutic target for TBI treatment.
