Bioengineered. 2022 May;13(5):11503-11516.doi: 10.1080/21655979.2022.2068737. (IF3.269)

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TNF-like weak inducer of apoptosis / nuclear factor κB axis feedback loop promotes spinal cord injury by inducing astrocyte activation

Dexiang Ban  1 Peng Yu  1 Zhenyang Xiang  1 Yang Liu  1


Free PMC article


Non-canonical signaling pathways have been proved to act as potent sites of astrocytes osmotic expanding or proliferation, which promotes the regeneration of axons in areas with non-neural spinal cord injury (SCI). However, the relevant signal pathway that induces autophagic cell death in astrocytes and its function relative to the TNF-like weak inducer of apoptosis/nuclear factor κB (TWEAK/NF-κB) axis remains elusive. The SCI model was established by vertically striking the spinal cord according to Allen’s model. Astrocytes and neuronal cells were prepared from spinal cells extracted from spinal cord tissues of SCI or normal C57BL/6 newborn mice. After co-culturing astrocytes and neurons, cell viability and autophagy were determined by CCK-8, transmission electron microscopy (TEM), and western blot. The expression of TWEAK, NF-κB and inflammatory cytokines was confirmed by qRT-PCR, western blot, Immunofluorescence and ELISA assay. Chromatin immunoprecipitation (CHIP) was used to evaluate the interaction between TWEAK and NF-κB. Our results demonstrated that knockdown of TWEAK and NF-κB inhibited secretion of high levels of TNF-α/IL-1β, partially counteracted by adding Rap. TWEAK/NF-κB was the positive correlation feedback loop regulating the proliferation and autophagy of astrocytes involved in SCI. Moreover, restraining the excess growth of astrocytes was beneficial to the growth of neurons. Collectively, our findings illustrated that the TWEAK/NF-κB pathway might act as a positive modulator of SCI by inducing astrocyte activation, shedding new insights for SCI treatment.

Keywords: NF-κB; Spinal cord injury (SCI); TWEAK; astrocytes; autophagy.