Serum Caspase-1 as an Independent Prognostic Factor in Traumatic Brain Injured Patients

Pérez-Bárcena, Jon; Pilar, Javier Rodríguez; Salazar, Osman; Crespı́, Catalina; Frontera, Guillem; Novo, Mariana Andrea; Guardiola, María B; Llompart‐Pou, Juan Antonio; Ibáñez, Javier; Vaccari, Juan Pablo de Rivero

doi:10.1007/s12028-021-01340-y

Cited by 12 publications

(11 citation statements)

References 23 publications

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“…Elevated rates of isovolumic relaxation time and higher apical strain in TBI patients compared to controls [31] have been measured using echocardiography. Additionally, our previous studies have shown that inflammasome signaling proteins are useful biomarkers of TBI [46,[57][58][59]. Our current findings, indicating that adoptive transfer of EVs from TBI patients into cardiovascular cells activates the inflammasome, reinforce our previous work showing that EVs released after TBI also trigger an inflammatory response consistent with acute lung injury [7,28,29].…”

Section: Discussionsupporting

confidence: 89%

Neural–Cardiac Inflammasome Axis after Traumatic Brain Injury

Keane,

Hadad,

Scott

et al. 2023

Pharmaceuticals

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Traumatic brain injury (TBI) affects not only the brain but also peripheral organs like the heart and the lungs, which influences long-term outcomes. A heightened systemic inflammatory response is often induced after TBI, but the underlying pathomechanisms that contribute to co-morbidities remain poorly understood. Here, we investigated whether extracellular vehicles (EVs) containing inflammasome proteins are released after severe controlled cortical impact (CCI) in C57BL/6 mice and cause activation of inflammasomes in the heart that result in tissue damage. The atrium of injured mice at 3 days after TBI showed a significant increase in the levels of the inflammasome proteins AIM2, ASC, caspases-1, -8 and -11, whereas IL-1β was increased in the ventricles. Additionally, the injured cortex showed a significant increase in IL-1β, ASC, caspases-1, -8 and -11 and pyrin at 3 days after injury when compared to the sham. Serum-derived extracellular vesicles (EVs) from injured patients were characterized with nanoparticle tracking analysis and Ella Simple Plex and showed elevated levels of the inflammasome proteins caspase-1, ASC and IL-18. Mass spectrometry of serum-derived EVs from mice after TBI revealed a variety of complement- and cardiovascular-related signaling proteins. Moreover, adoptive transfer of serum-derived EVs from TBI patients resulted in inflammasome activation in cardiac cells in culture. Thus, TBI elicits inflammasome activation, primarily in the atrium, that is mediated, in part, by EVs that contain inflammasome- and complement-related signaling proteins that are released into serum and contribute to peripheral organ systemic inflammation, which increases inflammasome activation in the heart.

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Section: Discussionsupporting

confidence: 89%

Neural–Cardiac Inflammasome Axis after Traumatic Brain Injury

Keane,

Hadad,

Scott

et al. 2023

Pharmaceuticals

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“…NLRP3 complex is mainly located in microglia [ 40 ] and after assembly and activation, pro-caspase 1 is proteolytically processed into its active form and in turn, it converts pro-IL-1β and pro-IL-18 into IL-1β and IL-18 pro-inflammatory cytokines [ 9 , 10 ]. High levels of NLRP3, caspase-1, IL-1β and IL-18 have been detected in the serum of TBI patients [ 41 , 42 ] as well as in the injured cerebral cortex in a murine model of TBI [ 43 ]. In our research, 21 days after inducing TBI, transcriptional levels of NLRP3 complex genes were higher in IS compared to NO IS in swine 1, except for IL-1β, for which the levels were similar.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Inflammatory Response by Electromagnetic Field Stimulation in Traumatic Brain Injury in Yucatan Swine

Mendoza-Mari,

Rai,

M. Radwan

et al. 2024

J Spine Res Surg

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Traumatic brain injury is a leading cause of disability and death worldwide and represents a high economic burden for families and national health systems. After mechanical impact to the head, the first stage of the damage comprising edema, physical damage, and cell loss gives rise to a second phase characterized by glial activation, increased oxidative stress and excitotoxicity, mitochondrial damage, and exacerbated neuroinflammatory state, among other molecular calamities. Inflammation strongly influences the molecular events involved in the pathogenesis of TBI. Therefore, several components of the inflammatory cascade have been targeted in experimental therapies. Application of Electromagnetic Field (EMF) stimulation has been found to be effective in some inflammatory conditions. However, its effect in the neuronal recovery after TBI is not known. In this pilot study, Yucatan miniswine were subjected to TBI using controlled cortical impact approach. EMF stimulation via a helmet was applied immediately or two days after mechanical impact. Three weeks later, inflammatory markers were assessed in the brain tissues of injured and contralateral non-injured areas of control and EMF-treated animals by histomorphometry, immunohistochemistry, RT-qPCR, Western blot, and ELISA. Our results revealed that EMF stimulation induced beneficial effect with the preservation of neuronal tissue morphology as well as the reduction of inflammatory markers at the transcriptional and translational levels. Immediate EMF application showed better resolution of inflammation. Although further studies are warranted, our findings contribute to the notion that EMF stimulation could be an effective therapeutic approach in TBI patients.

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“…Our results with VAMP8 indicate that in such a condition, the release of proteases could be increased, which could contribute to the presence of Tau fragments in the CSF. Indeed, the presence of caspase activity was reported in CSF of patients suffering from dementia and traumatic brain injury ( Harter et al, 2001 ; Albrecht et al, 2009 ) ( Perez-Barcena et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Pilliod

Gélinas-Faucher

Leclerc

2022

Front. Cell Dev. Biol.

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In Alzheimer’s disease, Tau, a microtubule-associated protein, becomes hyperphosphorylated, detaches from microtubules, and accumulates in the somato-dendritic compartment where it forms insoluble aggregates. Tau also accumulates in the CSF of patients indicating that it is released by neurons. Consistent with this, several laboratories including ours have shown that Tau is secreted by neurons through unconventional secretory pathways. Recently, we reported that VAMP8, an R-SNARE found on late endosomes, increased Tau secretion and that secreted Tau was cleaved at the C-terminal. In the present study, we examined whether the increase of Tau secretion by VAMP8 affected its intra- and extracellular cleavage. Upon VAMP8 overexpression, an increase of Tau cleaved by caspase-3 in the cell lysate and medium was observed. This was correlated to an increase of active caspase-3 in the cell lysate and medium. Using a Tau mutant not cleavable by caspase-3, we demonstrated that Tau cleavage by caspase-3 was not necessary for its secretion upon VAMP8 overexpression. By adding recombinant Tau to the culture medium, we demonstrated that extracellular Tau cleavage by caspase-3 could occur because of the release of active caspase-3, which was the highest when VAMP8 was overexpressed. When cleavage of Tau by caspase-3 was prevented by using a non-cleavable mutant, secreted Tau was still cleaved at the C-terminal, the asparagine N410 contributing to it. Lastly, we demonstrated that N-terminal of Tau regulated the secretion pattern of a Tau fragment containing the microtubule-binding domain and the C-terminal of Tau upon VAMP8 overexpression. Collectively, the above observations indicate that VAMP8 overexpression affects the intra- and extracellular cleavage pattern of Tau.

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Serum Caspase-1 as an Independent Prognostic Factor in Traumatic Brain Injured Patients

Cited by 12 publications

References 23 publications

Neural–Cardiac Inflammasome Axis after Traumatic Brain Injury

Neural–Cardiac Inflammasome Axis after Traumatic Brain Injury

Modulation of Inflammatory Response by Electromagnetic Field Stimulation in Traumatic Brain Injury in Yucatan Swine

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

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