Neuropathic pain after spinal cord injury lacks any effective treatments, often leading to chronic pain. This study tested whether the daily administration of fully characterized polyphenolic extracts from grape stalks and coffee could prevent both reflexive and non-reflexive chronic neuropathic pain in spinal cord-injured mice by modulating the neuroimmune axis. Female CD1 mice underwent mild spinal cord contusion and received intraperitoneal extracts in weeks one, three, and six post-surgery. Reflexive pain responses were assessed weekly for up to 10 weeks, and non-reflexive pain was evaluated at the study's end. Neuroimmune crosstalk was investigated, focusing on glial activation and the expression of CCL2/CCR2 and CX3CL1/CX3CR1 in supraspinal pain-related areas, including the periaqueductal gray, rostral ventromedial medulla, anterior cingulate cortex, and amygdala. Repeated treatments prevented mechanical allodynia and thermal hyperalgesia, and also modulated non-reflexive pain. Moreover, they reduced supraspinal gliosis and regulated CCL2/CCR2 and CX3CL1/CX3CR1 signaling. Overall, the combination of polyphenols in these extracts may offer a promising pharmacological strategy to prevent chronic reflexive and non-reflexive pain responses by modifying central sensitization markers, not only at the contusion site but also in key supraspinal regions implicated in neuropathic pain. Overall, these data highlight the potential of polyphenolic extracts for spinal cord injury-induced chronic neuropathic pain.
- Klíčová slova
- chemokines, chronic neuropathic pain, glia, neuroinflammation, polyphenols, spinal cord injury,
- MeSH
- chemokin CCL2 metabolismus MeSH
- chemokin CX3CL1 metabolismus MeSH
- CX3C chemokinový receptor 1 metabolismus MeSH
- glióza * farmakoterapie metabolismus MeSH
- hyperalgezie farmakoterapie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- neuralgie * farmakoterapie metabolismus etiologie prevence a kontrola MeSH
- polyfenoly * farmakologie aplikace a dávkování MeSH
- poranění míchy * komplikace farmakoterapie metabolismus MeSH
- receptory CCR2 metabolismus MeSH
- rostlinné extrakty * farmakologie aplikace a dávkování MeSH
- signální transdukce * účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Ccl2 protein, mouse MeSH Prohlížeč
- Ccr2 protein, mouse MeSH Prohlížeč
- chemokin CCL2 MeSH
- chemokin CX3CL1 MeSH
- CX3C chemokinový receptor 1 MeSH
- Cx3cr1 protein, mouse MeSH Prohlížeč
- polyfenoly * MeSH
- receptory CCR2 MeSH
- rostlinné extrakty * MeSH
The cellular distribution and changes in CX3CL1/fractalkine and its receptor CX3CR1 protein levels in the trigeminal subnucleus caudalis (TSC) of rats with unilateral infraorbital nerve ligation (IONL) were investigated on postoperation days 1, 3, 7, and 14 (POD1, POD3, POD7, and POD14, respectively) and compared with those of sham-operated and naïve controls. Behavioral tests revealed a significant increase in tactile hypersensitivity bilaterally in the vibrissal pads of both sham- and IONL-operated animals from POD1 to POD7, with a trend towards normalization in sham controls at POD14. Image analysis revealed increased CX3CL1 immunofluorescence (IF) intensities bilaterally in the TSC neurons of both sham- and IONL-operated rats at all survival periods. Reactive astrocytes in the ipsilateral TSC also displayed CX3CL1-IF from POD3 to POD14. At POD1 and POD3, microglial cells showed high levels of CX3CR1-IF, which decreased by POD7 and POD14. Conversely, CX3CR1 was increased in TSC neurons and reactive astrocytes at POD7 and POD14, which coincided with high levels of CX3CL1-IF and ADAM17-IF. This indicates that CX3CL1/CX3CR1 may be involved in reciprocal signaling between TSC neurons and reactive astrocytes. The level of CatS-IF in microglial cells suggests that soluble CX3CL1 may be involved in neuron-microglial cell signaling at POD3 and POD7, while ADAM17 allows this release at all studied time points. These results indicate an extended CX3CL1/CX3CR1 signaling axis and its role in the crosstalk between TSC neurons and glial cells during the development of trigeminal neuropathic pain.
- Klíčová slova
- chemokine receptors, chemokines, image analysis, immunohistochemistry, microglial cells, neurons, reactive astroglia,
- MeSH
- astrocyty metabolismus MeSH
- chemokin CX3CL1 * metabolismus MeSH
- CX3C chemokinový receptor 1 * metabolismus genetika MeSH
- krysa rodu Rattus MeSH
- mikroglie metabolismus MeSH
- neuralgie trigeminu metabolismus patologie MeSH
- neuralgie metabolismus patologie MeSH
- neurony metabolismus MeSH
- potkani Sprague-Dawley MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- chemokin CX3CL1 * MeSH
- CX3C chemokinový receptor 1 * MeSH
- Cx3cl1 protein, rat MeSH Prohlížeč
- CX3CR1 protein, rat MeSH Prohlížeč
OBJECTIVE: The pathophysiological processes leading to epileptogenesis and pharmacoresistance in epilepsy have been the subject of extensive preclinical and clinical research. The main impact on clinical practice is the development of new targeted therapies for epilepsy. We studied the importance of neuroinflammation in the development of epileptogenesis and pharmacoresistance in childhood epilepsy patients. METHODS: A cross-sectional study conducted at two epilepsy centers in the Czech Republic compared 22 pharmacoresistant patients and 4 pharmacodependent patients to 9 controls. We analyzed the ProcartaPlex™ 9-Plex immunoassay panel consisting of interleukin (IL)-6, IL-8, IL-10, IL-18, CXCL10/IP-10, monocyte chemoattractant protein 1 (CCL2/MCP-1), B lymphocyte chemoattractant (BLC), tumor necrosis factor-alpha (TNF-α), and chemokine (C-X3-X motif) ligand 1 (fractalkine/CXC3CL1) to determine their alterations in cerebrospinal fluid (CSF) and blood plasma, concurrently. RESULTS: The analysis of 21 paired CSF and plasma samples in pharmacoresistant patients compared to controls revealed a significant elevation of CCL2/MCP-1 in CSF (p < 0.000512) and plasma (p < 0.00.017). Higher levels of fractalkine/CXC3CL1 were revealed in the plasma of pharmacoresistant patients than in controls (p < 0.0704), and we determined an upward trend in CSF IL-8 levels (p < 0.08). No significant differences in CSF and plasma levels were detected between pharmacodependent patients and controls. CONCLUSION: Elevated CCL2/MCP-1 in CSF and plasma, elevated levels of fractalkine/CXC3CL1 in CSF, and a trend toward elevated IL-8 in the CSF of patients with pharmacoresistant epilepsy indicate these cytokines as potential biomarkers of epileptogenesis and pharmacoresistance. CCL2/MCP-1was detected in blood plasma; this assessment may be easily achieved in clinical practice without the invasiveness of a spinal tap. However, due to the complexity of neuroinflammation in epilepsy, further studies are warranted to confirm our findings.
- Klíčová slova
- Chemokine, Cytokine, Epileptogenesis, Interleukin, Pharmacodependent, Pharmacoresistant,
- MeSH
- biologické markery mozkomíšní mok MeSH
- chemokin CCL2 * mozkomíšní mok MeSH
- chemokin CX3CL1 MeSH
- epilepsie * diagnóza farmakoterapie MeSH
- interleukin-8 mozkomíšní mok MeSH
- lidé MeSH
- neurozánětlivé nemoci MeSH
- průřezové studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biologické markery MeSH
- CCL2 protein, human MeSH Prohlížeč
- chemokin CCL2 * MeSH
- chemokin CX3CL1 MeSH
- interleukin-8 MeSH
Kidney allograft transplantation improved the prognosis and quality of life of patients with end-stage renal diseases but the occurrence of acute rejection represents a limitation of the final outcome. Noninvasive biomarkers are needed as well as further advancements in the understanding of immune mechanisms of reaction to the allograft. Our study of 138 patients focused on one-year monitoring of serum concentrations of 12 chemokines regulating the recruitment of different immune cells into transplanted allograft and on in vitro regulation of the same chemokines release by interactions of renal proximal epithelial cells with monocyte/macrophage cell line stimulated with TNF alpha. In a group of 44 patients with acute rejection, higher serum pretransplant levels of CXCL1, CXCL5, CXCL6, CCL2, CCL21, and particularly CXCL10 and CX3CL1(both p < 0.001) were found suggesting their higher proinflammatory status as compared to subjects with the uncomplicated outcome. In samples collected at the day of biopsy positive for acute rejection, chemokines CXCL9 and CXCL11 attracting preferentially Th1 lymphocytes were found to be upregulated. In our in vitro model with TNF alpha induction, renal proximal epithelial cells seemed to be a more potent source of chemokines attracting neutrophils as compared to monocyte/macrophage cell line but the coculture of these cells potentiated release of neutrophilic chemokines CXCL5 and CXCL6. Similar augmentation of chemokine production was found also in the case of CCL2. On the other hand, adding of monocytes/macrophages to a culture of renal epithelial cells suppressed the release of CXCL10 and CXCL11 attracting T lymphocytes. We assume from our data that in kidney allograft transplantation, chemokines attracting neutrophils, T lymphocytes, and monocytes are induced simultaneously and measurement some of them in combination might be used as biomarkers of acute rejection. Mutual cell-cell interactions of immune cells with renal parenchyma seem to be important for fine regulation of chemokine release.
- MeSH
- alografty MeSH
- chemokin CCL2 krev MeSH
- chemokin CCL21 krev MeSH
- chemokin CX3CL1 krev MeSH
- chemokin CXCL1 krev MeSH
- chemokin CXCL10 krev MeSH
- chemokin CXCL11 krev MeSH
- chemokin CXCL5 krev MeSH
- chemokin CXCL6 krev MeSH
- chemokin CXCL9 krev MeSH
- chemokiny krev MeSH
- kvalita života MeSH
- lidé MeSH
- rejekce štěpu krev imunologie MeSH
- Th1 buňky metabolismus MeSH
- transplantace ledvin škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- chemokin CCL2 MeSH
- chemokin CCL21 MeSH
- chemokin CX3CL1 MeSH
- chemokin CXCL1 MeSH
- chemokin CXCL10 MeSH
- chemokin CXCL11 MeSH
- chemokin CXCL5 MeSH
- chemokin CXCL6 MeSH
- chemokin CXCL9 MeSH
- chemokiny MeSH
- CXCL1 protein, human MeSH Prohlížeč
Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of pro-inflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-) mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.
- MeSH
- chemokin CX3CL1 metabolismus MeSH
- cytokiny metabolismus MeSH
- idiopatické střevní záněty imunologie MeSH
- infiltrace neutrofily genetika MeSH
- kolitida chemicky indukované imunologie MeSH
- kolon imunologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- makrofágy imunologie MeSH
- mediátory zánětu metabolismus MeSH
- metaloproteinasy secernované do matrix genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- pohyb buněk MeSH
- přirozená imunita MeSH
- progrese nemoci MeSH
- síran dextranu MeSH
- střevní sliznice imunologie patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chemokin CX3CL1 MeSH
- Cx3cl1 protein, mouse MeSH Prohlížeč
- cytokiny MeSH
- matrix metalloproteinase 19 MeSH Prohlížeč
- mediátory zánětu MeSH
- metaloproteinasy secernované do matrix MeSH
- síran dextranu MeSH
