The role of S100B/RAGE-enhanced ADAM17 activation in endothelial glycocalyx shedding after traumatic brain injury

Abstract

Background Traumatic brain injury (TBI) remains one of the main causes for disability and death worldwide. While the primary mechanical injury cannot be avoided, the prevention of secondary injury is the focus of TBI research. Present study aimed to elucidate the effects and mechanisms of S100B and its receptor RAGE on mediating secondary injury after TBI. Methods This study established TBI animal model by fluid percussion injury in rats, cell model by stretch-injured in astrocytes, and endothelial injury model with conditioned medium stimulation. Pharmacological intervention was applied to interfere the activities of S100B/RAGE/ADAM17 signaling pathway, respectively. The expressions or contents of S100B, RAGE, syndecan-1 and ADAM17 in brain and serum, as well as in cultured cells and medium, were detected by western blot. The distribution of relative molecules was observed with immunofluorescence. Results We found that TBI could activate the release of S100B, mostly from astrocytes, and S100B and RAGE could mutually regulate their expression and activation. Most importantly, present study revealed an obvious increase of syndecan-1 in rat serum or in endothelial cultured medium after injury, and a significant decrease in tissue and in cultured endothelial cells, indicating TBI-induced shedding of endothelial glycocalyx. The data further proved that the activation of S100B/RAGE signaling could promote the shedding of endothelial glycocalyx by enhancing the expression, translocation and activity of ADAM17, an important sheddase, in endothelial cells. The damage of endothelial glycocalyx consequently aggravated blood brain barrier (BBB) dysfunction and systemic vascular hyper-permeability, overall resulting in secondary brain and lung injury. Conclusions TBI triggers the activation of S100B/RAGE signal pathway. The regulation S100B/RAGE on ADAM17 expression, translocation and activation further promotes the shedding of endothelial glycocalyx, aggravates the dysfunction of BBB, and increases the vascular permeability, leading to secondary brain and lung injury. Present study may open a new corridor for the more in-depth understanding of the molecular processes responsible for cerebral and systemic vascular barrier impairment and secondary injury after TBI.

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…The cleavage and release of substrates (inflammatory cytokines, growth factors, receptors, adhesion molecules, and others) for ADAM17 may result in different functions of substrate proteins. Some substrate proteins, such as glycocalyx (104), TNFR (173,178), and JAM-A/FIIR (156), are shed by ADAM17 in the form of active molecules. Glycocalyx is a polysaccharide protein complex that covers the aperture membrane surface of vascular endothelial cells and regulates the homeostasis of the cytoplasmic membrane through proteoglycan-glycoprotein attachment to endothelial cells.…”

Tanshione IIA reduces AQP4 over-clustering in the plasma membrane and astrocyte swelling after oxygen-glucose deprivation and reoxygenation by inhibition of the HMGB1/RAGE/NF-κB/IL-6 pro-inflammatory axis

“…Secreted HMGB1 binds to its receptors RAGE, TLR2, and TLR4 to activate downstream signaling pathways and release in ammatory factors that lead to further damage (Rauvala and Rouhiainen, 2007). Numerous studies have demonstrated that genetic or pharmacological inhibition of RAGE in animal models attenuate brain edema after injury and inhibit pro-in ammatory response (Postolache et al, 2020;Zou et al, 2022). Thus, we studied whether RAGE was involved in TSO IIA-mediated reduction of astrocyte swelling.…”

Antioxidant-based neuroprotective effect of dimethylsulfoxide against induced traumatic brain injury in a rats model

“…It has been correlated with injury severity in hospitalized human patients (Hendoui et al, 2013). High levels of S100B can stimulate inflammatory injury ( Reali et al, 2005 ; Zou et al, 2022 ). S100 B has cytokine-like activities and can interact with the receptor for the advanced glycation end product (RAGE) ( Mori et al, 2008 ; Zou et al, 2022 ).…”

“…High levels of S100B can stimulate inflammatory injury ( Reali et al, 2005 ; Zou et al, 2022 ). S100 B has cytokine-like activities and can interact with the receptor for the advanced glycation end product (RAGE) ( Mori et al, 2008 ; Zou et al, 2022 ). Therefore, the decreased concentration of S100B observed in the DMSO-treated rats could be due to its antioxidative effect.…”