Occlusal Trauma Induces Neuroimmune Crosstalk for a Pain State

2021 ◽  
pp. 002203452110394
Author(s):  
H.B. Abdalla ◽  
M.H. Napimoga ◽  
C.A. Trindade-da-Silva ◽  
M. Guimarães ◽  
M. Lopes ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Trigeminal Ganglia ◽  
Nociceptive Response ◽  
Mrna Levels ◽  
Neuronal Excitation ◽  
Erk Phosphorylation ◽  
Tnf Α ◽  
Perk Expression ◽  
Pain State ◽  
The Impact

Temporomandibular joint (TMJ) disorder caused by occlusal trauma is one of the most controversial topics in dentistry. Experimental traumatic occlusion (ETO) induced by metal crowns cemented to mandibular first molars in rats causes a long-lasting nociceptive response. This study aimed to elucidate whether ETO generates an increase in inflammatory mediators in the TMJ. In addition, the impact of ETO on trigeminal ganglia, neurotransmitter release, and satellite glial cell (SGC) activation was investigated. ELISA revealed enhanced inflammatory mediators, including TNF-α, IL-1β, IL-6, CX3CL1, and ADAM-17 by Western blotting, in periarticular TMJ tissue after 28 d of ETO. In the trigeminal ganglia, ETO groups increased the release of the neurotransmitters substance P and glutamate. Overexpression of the AMPA receptor and upregulation of NMDA were observed in the 0.4- and 0.7-mm ETO groups, respectively, highlighting enhanced neuronal excitation. Increased IL-1β and COX-2 mRNA levels in the 0.7-mm ETO group confirmed trigeminal ganglia SGC activation. Immunofluorescence and electrophoresis of SGC revealed increased pERK expression in the 0.7-mm ETO group. ERK phosphorylation was shown to be nociceptive specific, with its upregulation occurring in cases of chronic inflammatory pain. Increased PKA mRNA levels were observed in the 0.4-mm ETO group, while CREB mRNA levels were upregulated for both ETO groups. Electrophoresis showed overexpression of sodium channel Nav 1.7 in the 0.7-mm ETO group, while immunofluorescence revealed that Nav 1.7 is expressed in sensory trigeminal ganglia cells. The results of this study suggest that occlusal trauma induces neuroimmune crosstalk, with synthesis of proinflammatory/pronociceptive mediators, which increases neuronal activity in trigeminal ganglia via the activation of an inflammatory response cascade to develop a persistent neuroinflammatory state that leads to central sensitization.

Regulation of human airway mucins by acrolein and inflammatory mediators

1999 ◽  
Vol 276 (4) ◽  
pp. L549-L555 ◽  
Author(s):  
Michael T. Borchers ◽  
Michael P. Carty ◽  
George D. Leikauf
Keyword(s):  
Inflammatory Mediators ◽  
Control Level ◽  
Carcinoma Cells ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Major Mechanism ◽  
Lung Carcinoma Cells ◽  
Tnf Α ◽  
Human Lung Carcinoma ◽  
Factor Α

Bronchitis, asthma, and cystic fibrosis, marked by inflammation and mucus hypersecretion, can be caused or exacerbated by airway pathogens or irritants including acrolein, an aldehyde present in tobacco smoke. To determine whether acrolein and inflammatory mediators alter mucin gene expression, steady-state mRNA levels of two airway mucins, MUC5AC and MUC5B, were measured (by RT-PCR) in human lung carcinoma cells (NCI-H292). MUC5AC mRNA levels increased after ≥0.01 nM acrolein, 10 μM prostaglandin E2 or 15-hydroxyeicosatetraenoic acid, 1.0 nM tumor necrosis factor-α (TNF-α), or 10 nM phorbol 12-myristate 13-acetate (a protein kinase C activator). In contrast, MUC5B mRNA levels, although easily detected, were unaffected by these agonists, suggesting that irritants and associated inflammatory mediators increase mucin biosynthesis by inducing MUC5ACmessage levels, whereas MUC5B is constitutively expressed. When transcription was inhibited, TNF-α exposure increased MUC5AC message half-life compared with control level, suggesting that transcript stabilization is a major mechanism controlling increased MUC5AC message levels. Together, these findings imply that irritants like acrolein can directly and indirectly (via inflammatory mediators) increase airway mucin transcripts in epithelial cells.

scholarly journals Tumor necrosis factor-α induces a biphasic change in claudin-2 expression in tubular epithelial cells: role in barrier functions

2015 ◽  
Vol 309 (1) ◽  
pp. C38-C50 ◽  
Author(s):  
Yasaman Amoozadeh ◽  
Qinghong Dan ◽  
Jenny Xiao ◽  
Faiza Waheed ◽  
Katalin Szászi
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mrna Levels ◽  
Tnf Α ◽  
Biphasic Effect ◽  
Early Increase ◽  
Factor Α ◽  
The Impact ◽  
Necrosis Factor

The inflammatory cytokine tumor necrosis factor-α (TNF-α) is a pathogenic factor in acute and chronic kidney disease. TNF-α is known to alter expression of epithelial tight junction (TJ) proteins; however, the underlying mechanisms and the impact of this effect on epithelial functions remain poorly defined. Here we describe a novel biphasic effect of TNF-α on TJ protein expression. In LLC-PK1 tubular cells, short-term (1–6 h) TNF-α treatment selectively elevated the expression of the channel-forming TJ protein claudin-2. In contrast, prolonged (>8 h) TNF-α treatment caused a marked downregulation in claudin-2 and an increase in claudin-1, -4, and -7. The early increase and the late decrease in claudin-2 expression involved distinct mechanisms. TNF-α slowed claudin-2 degradation through ERK, causing the early increase. This increase was also mediated by the EGF receptor and RhoA and Rho kinase. In contrast, prolonged TNF-α treatment reduced claudin-2 mRNA levels and promoter activity independent from these signaling pathways. Electric Cell-substrate Impedance Sensing measurements revealed that TNF-α also exerted a biphasic effect on transepithelial resistance (TER) with an initial decrease and a late increase. Thus there was a good temporal correlation between TNF-α-induced claudin-2 protein and TER changes. Indeed, silencing experiments showed that the late TER increase was at least in part caused by reduced claudin-2 expression. Surprisingly, however, claudin-2 silencing did not prevent the early TER drop. Taken together, the TNF-α-induced changes in claudin-2 levels might contribute to TER changes and could also play a role in newly described functions of claudin-2 such as proliferation regulation.

Inflammatory Mediators Are Increased in Leukocytes of IVS-I-6 (T→C) Homozygous β-Thalassemia Intermedia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4068-4068
Author(s):  
Marcos André C Bezerra ◽  
Carla Fernanda Franco-Penteado ◽  
Carolina Lanaro ◽  
Mariana R. B. Mello ◽  
Sheley Gambero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Mediators ◽  
Plasma Levels ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Thalassemia Intermedia ◽  
Gene Expressions ◽  
Survivin Protein ◽  
Tnf Α

Abstract Abstract 4068 Poster Board III-1003 Thalassemia is characterized by chronic inflammatory state and inflammation may play an important role in the pathogenesis of this diseases. Endothelial adhesion molecules, reactive oxygen species (ROS), C reactive protein and cytokines were increased in thalassemia patients. In addition, adherence of red blood cells, neutrophils and platelets to extracellular matrix protein and neutrophils chemotaxis has been shown to be markedly enhanced in β-thalassemia intermedia (TI) patients. Although alterations in inflammatory biomarkers have been related previously, most studies have been carried out with patients either polytransfused, receiving hydroxyurea (HU) therapy or with β-thalassemia major. An investigation of the role of inflammatory mediators in TI may further contribute to the understanding the pathogenesis of the disease. The aim of this study was to determine plasma levels and leukocyte gene expressions of inflammatory mediators/cytokines in neutrophils and mononuclear cells (MC) of untransfused patients and those not on HU therapy TI IVS-I-6 (T→C) homozygous (n≤20) and healthy controls (n≤20). ELISA was used to determine cytokine production; survivin protein expression was determined by flow cytometry with survivin-specific antibodies and qRT-PCR analysis to examine gene expression of cytokines, the protective enzyme heme oxygenase-1 (HO-1) and BIRC-5 (survivin). TNF-α, IL-6, IL-8 and IL-1β plasma levels were significantly higher in the plasma of TI individuals, when compared to control individuals (3.78 ± 0.4 vs 2.18 ± 0.3; 0.93 ± 0.1 vs 0.46 ± 0.08; 18.97 ± 5.6 vs 6.09 ± 1.1; 1.88 ± 0.7 vs 0.34 ± 0.05, pg/ml, P<0.05, respectively). Survivin protein levels in MC from TI was significantly increased when compared to healthy controls (45.9 ± 1.8 × 39.74 ± 1.74, MFI, P=0.022, respectively). IL-8, IL-10 and HO-1 gene expressions were unaltered in TI neutrophils (0.31 ± 0.13; 0.1 ± 0.08; 0.44 ± 0.2; A.U., respectively) compared to healthy controls neutrophils (0.45 ± 0.13; 0.17 ± 0.04; 0.22 ± 0.07, A.U., respectively), however in TI neutrophils gene expression of TNF-α was significantly higher than those of control subjects (0.76 ± 0.3 vs 0.24 ± 0.05, A.U., P=0.03, respectively). Expressions of genes encoding IL-8, IL-10, HO-1 and BIRC-5 were higher in MC of TI patients, compared with those of healthy controls (0.75 ± 0.3 vs 0.02 ± 0.005; 0.36 ± 0.07 vs 0.19 ± 0.04; 1.69 ± 0.28 vs 0.27 ± 0.09; 1.13 ± 0.12 vs 0.55 ± 0.17, A.U., P=0.02; P=0.04; P=0.0002, P=0.019, respectively). No significant alterations in the TNF-α mRNA levels were found in the MC of TI patients compared with healthy controls (0.21 ± 0.06 vs 0.16 ± 0.03, A.U., respectively). Taken together our data showed a higher production of inflammatory cytokines in MC, which could contribute to the pathophysiology of TI. Anti-inflammatory mechanisms (IL-10 and HO-1) were also up-regulated in these individuals, indicating efforts to counteract these alterations. These results are strong indications of the presence of chronic inflammatory processes and knowledge of these pathways may contribute to the understanding of the pathophysiology of TI. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mesenteric Lymph Duct Drainage Attenuates Lung Inflammatory Injury and Inhibits Endothelial Cell Apoptosis in Septic Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Yongjun Liu ◽  
Chuanxi Chen ◽  
Qing Sun ◽  
Huadong Sun ◽  
Ning Liu ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Inflammatory Mediators ◽  
Cell Apoptosis ◽  
Mrna Levels ◽  
Endothelial Cell Apoptosis ◽  
Lymph Drainage ◽  
Inflammatory Injury ◽  
Mesenteric Lymph ◽  
Tnf Α ◽  
Lymph Duct

The present study was to investigate the effect of mesenteric lymph duct drainage on lung inflammatory response, histological alteration, and endothelial cell apoptosis in septic rats. Animals were randomly assigned into four groups: control, sham surgery, sepsis, and sepsis plus mesenteric lymph drainage. We used the colon ascendens stent peritonitis (CASP) procedure to induce the septic model in rats, and mesenteric lymph drainage was performed with a polyethylene (PE) catheter inserted into mesenteric lymphatic. The animals were sacrificed at the end of CASP in 6 h. The mRNA expression levels of inflammatory mediators were measured by qPCR, and the histologic damage were evaluated by the pathological score method. It was found that mesenteric lymph drainage significantly reduced the expression of TNF-α, IL-1β, and IL-6 mRNA in the lung. Pulmonary interstitial edema and infiltration of inflammatory cells were alleviated by mesenteric lymph drainage. Moreover, increased mRNA levels of TNF-α, IL-1β, IL-6 mRNA, and apoptotic rate were observed in PMVECs treated with septic lymph. These results indicate that mesenteric lymph duct drainage significantly attenuated lung inflammatory injury by decreasing the expression of pivotal inflammatory mediators and inhibiting endothelial apoptosis to preserve the pulmonary barrier function in septic rats.

scholarly journals Fatal Dengue Cases Reveal Brain Injury and Viral Replication in Brain-Resident Cells Associated with the Local Production of Pro-Inflammatory Mediators

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 603 ◽  
Author(s):  
Natália Salomão ◽  
Kíssila Rabelo ◽  
Carlos Basílio-de-Oliveira ◽  
Rodrigo Basílio-de-Oliveira ◽  
Luiz Geraldo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Mediators ◽  
Denv Infection ◽  
Microglial Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Lymphocytic Infiltrates ◽  
The Impact ◽  
Arboviral Disease

Dengue is an arboviral disease caused by dengue virus (DENV), which is transmitted to humans by Aedes aegypti mosquitoes. Infection by DENV most commonly results in a mild flu-like illness; however, the disease has been increasingly associated with neurological symptomatology. This association draws attention to further investigations on the impact of DENV infection in the host’s central nervous system. Here, we analyzed brain samples of three fatal dengue cases that occurred in 2002 during an outbreak in Rio de Janeiro, Brazil. Brain tissues of these cases were marked by histopathological alterations, such as degenerated neurons, demyelination, hemorrhage, edema, and increased numbers of astrocytes and microglial cells. Samples were also characterized by lymphocytic infiltrates mainly composed of CD8 T cells. DENV replication was evidenced in neurons, microglia and endothelial cells through immunohistochemistry and in situ hybridization techniques. Pro-inflammatory cytokines, such as TNF-α and IFN-γ were detected in microglia, while endothelial cells were marked by the expression of RANTES/CCL5. Cytoplasmic HMGB1 and the production of nitric oxide were also found in neurons and microglial cells. This work highlights the possible participation of several local pro-inflammatory mediators in the establishment of dengue neuropathogenesis.

Effect of garlic intake on inflammatory mediators: a systematic review and meta-analysis of randomised controlled trials

2020 ◽  
pp. postgradmedj-2019-137267
Author(s):  
Mehdi Koushki ◽  
Nasrin Amiri-Dashatan ◽  
Yasin Pourfarjam ◽  
Amir Hossein Doustimotlagh
Keyword(s):  
Systematic Review ◽  
Inflammatory Mediators ◽  
Metabolic Diseases ◽  
Meta Analysis ◽  
Random Effect ◽  
Sensitivity Analyses ◽  
Current Evidence ◽  
Cochrane Library ◽  
Tnf Α ◽  
The Impact

BackgroundGarlic is a species in the onion genus, Allium. Data have shown that garlic has anti-inflammatory activity; however, the findings are inconclusive and inconsistent. We aimed to evaluate the impact of garlic intake on inflammatory mediators through systematic review and meta-analysis of existing data.MethodsElectronic databases were completely investigated using databases of ISI Web of Science, Medline, Scopus, Cochrane Library and EMBASE until October 2019. A random effects model and the generic reverse variance procedure were used for quantitative data production. Sensitivity analyses and prespecified subgroup were done to evaluate potential heterogeneity. Random effect meta-regression was conducted to investigate the effects of possible confounders on the assessed effect size.ResultsTen trials with one observational study, including 530 participants, met the eligibility criteria. The findings showed reduction in the tumour necrosis factor alpha (TNF-α) (−0.31 pg/mL, 95% CI −1.07 to 0.46) and C reactive protein (CRP) levels (−0.20 mg/L, 95% CI −1.4 to 1.05) following supplementation with garlic, although it had no marked impact on the interleukin 6 (IL-6) level (0.37 pg/mL, 95% CI −0.58 to 1.33). In the subgroup analysis, we found that garlic supplementation significantly decreased TNF-α, highly sensitive CRP and IL-6 levels in subgroups of >8, >6 and ≥4 weeks of intervention duration, respectively, and dose of garlic consumption between 2 and 2.4 g/day.ConclusionThese findings suggested that current evidence may support garlic as an adjunct to pharmacological management of metabolic diseases.PROSPERO registration numberCRD42018108816.

scholarly journals Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition

2012 ◽  
Vol 107 (05) ◽  
pp. 884-894 ◽  
Author(s):  
Erik W. Holy ◽  
Giovanni G. Camici ◽  
Alexander Akhmedov ◽  
Simon F. Stämpfli ◽  
Barbara E. Stähli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Tissue Factor ◽  
Surface Activity ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Phosphatidylinositol 3 Kinase ◽  
Tnf Α ◽  
The Impact ◽  
Phosphatidylinositol 3

SummaryTissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.

scholarly journals Anti-Proliferative Activity of Glucagon-Like Peptide-1 Receptor Agonist on Obesity-Associated Breast Cancer: The Impact on Modulating Adipokines’ Expression in Adipocytes and Cancer Cells

Dose-Response ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 155932582199565
Author(s):  
Alaa A. Alanteet ◽  
Hala A. Attia ◽  
Sameerah Shaheen ◽  
Musaed Alfayez ◽  
Bisher Alshanawani
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Inflammatory Mediators ◽  
Mrna Levels ◽  
Obese Subjects ◽  
Glucagon Like Peptide 1 ◽  
Clinical Prevention ◽  
The Impact ◽  
Cells Cultured ◽  
Mcf 7

Obesity is associated with high risk and poor prognosis of breast cancer (BC). Obesity promotes BC cells proliferation via modulating the production of adipokines, including adiponectin (anti-neoplastic adipokine), leptin (carcinogenic adipokine) and inflammatory mediators. In the present study we investigated the anti-proliferative effects of liraglutide (LG; anti-diabetic and weight reducing drug) on MCF-7 human BC cells cultured in obese adipose tissue-derived stem cells-conditioned medium (ADSCs-CM) and whether this effect is mediated via modulating the adipokines in ADSCs and cancer cells. Proliferation was investigated using AlamarBlue viability test, colony forming assay and cell cycle analysis. Levels and expression of adipokines and their receptors were assayed using ELISA and RT-PCR. LG caused 48% inhibition of MCF-7 proliferation in obese ADSCs-CM, reduced the colony formation and induced G0/G1 phase arrest. LG also decreased the levels of inflammatory mediators, suppressed the expression of leptin, while increased mRNA levels of adiponectin and their receptors in obese ADSCs and cancer cells cultured in obese ADCSs-CM. In conclusion, LG could mitigate BC cell growth in obese subjects; therefore it could be used for clinical prevention and/or treatment of BC in obese subjects. It may assist to improve treatment outcomes and, reduce the mortality rate in obese patients with BC.

Abstract 619: Blockage Of Toll-Like Receptor 4 Inhibits Renin Stimulation Of NF-KB-Mediated Cytokine Signaling In Brain Neurons

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Zhiying Shan ◽  
Wei Yuan
Keyword(s):  
Inflammatory Mediators ◽  
Interleukin 1 ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Neurogenic Hypertension ◽  
Tnf Α ◽  
A Subunit ◽  
Stimulation Of

Toll-like receptor 4 (TLR4) has been shown to play an important role in inflammation and initiation and progression of cardiovascular pathologies. This, coupled with the observation that activation of the brain (pro)renin receptor (PRR) initiates NF-Kappa B (KB) -cytokine signaling to induce neurogenic hypertension has led us to hypothesize that brain PRR activation, in part, stimulates TLR4 to induce NF-KB-cytokine signal pathway. Thus, blockage of TLR4 should attenuate the expression of NF-KB and proinflammatory cytokines induced by PRR activation. To test this hypothesis, we harvested neuronal cells from neonatal Sprague Dawley rat brain that abundantly express PRR, and incubated with 20 nM of renin for 6 hours. Real time PCR was performed to analyze expression of NF-KB and other inflammatory mediators. Renin treatment resulted in significant increases in interleukin-1 β (IL-1β, 1200-fold), IL-6 (33-fold), tumor necrosis factor (TNF-α, 17-fold), leukemia inhibitory factor (LIF, 18-fold) and C-C ligand 5 (CCL5, 330-fold). In addition, the mRNA levels of P50, a subunit of NF-KB was increased by 5-fold, and nfkbia, a subunit of I-kappa B kinase (IKK), was increased by 7-fold. Furthermore, mRNA levels of inducible nitric oxide synthase (iNOS) was increased by 8000-fold, and a neuronal activation maker, c-FOS was increased by 28 fold as compared with control neurons. However, Quinazoline (10μM), a NF-KB activation inhibitor, effectively blocked renin-induced increases in IL-1β, IL-6, TNF-α, CCL5, iNOS and P50 by more than 85%, but failed to inhibit LIF, nfkbia and c-FOS. In contrast, renin stimulation of all the above genes (IL-1β, IL-6, TNF-α, CCL5, iNOS, LIF, P50, nfkbia and c-FOS) was almost entirely blocked (>90%) by the TLR4 inhibitor, TAK-242 (2 μM), indicating a novel PRR mediated activation of TLR4 signaling. This PRR regulation of neuronal inflammatory mediators and neuronal activity was not affected by AT1 receptor antagonist losartan, demonstrating that the effect is not mediated by PRR-induced Ang-II generation. Our studies suggest that PRR plays a central role in the development of inflammatory mediated neurogenic hypertension through activation of TLR4.

scholarly journals Oligomeric α-Synuclein induces skin degeneration in a reconstructed human epidermis model

2021 ◽  
Author(s):  
Julia T Oliveira ◽  
Rodrigo de Vecchi ◽  
Vanja Dakic ◽  
Gabriela Vitoria ◽  
Carolina Pedrosa ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Nuclear Translocation ◽  
Human Epidermis ◽  
Epidermal Keratinocytes ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Reconstructed Human Epidermis ◽  
Healthy Elderly ◽  
Tnf Α ◽  
The Impact

Cell senescence may promote epidermal inflammation and degeneration, termed as inflammaging, which is accompanied by keratinocyte loss, resulting in fine lines of wrinkles. Recent findings showed that healthy elderly skin expresses age- and neuron-related amyloidogenic proteins, such as tau, β-Amyloid34, and α-synuclein (α-Syn), typically found in patients with neurodegenerative diseases. These proteins form toxic aggregates that trigger inflammatory signals. Herein, we investigated the impact of oligomeric α-Syn (Oα-Syn) on the neurosphere (NP) and the reconstructed human epidermis (RHE) 3D models. First, we found the expression of α-Syn, β-Amyloid, and amyloid precursor protein (APP) in the RHE. Second, we challenged the RHE and NP with Oα-Syn, which decreased RHE regeneration, measured by the percentage of cell proliferation and thickness of the stratum basale, but did not affect NP neurite outgrowth. Oα-Syn did not decrease the number of human neonatal epidermal keratinocytes (HEKn) but, as seen for the RHE, it also decreased the proliferation of HEKn. We confirmed that the oligomeric, and not the monomeric α-Syn species, accounted for the proliferation-decreasing effect. Oα-Syn also increased the NF-κB nuclear translocation in HEKn analyzed by nucleus/cytoplasm NF-κB fluorescence intensity. In addition, Oα-Syn triggered inflammation in the RHE, by increasing the mRNA levels of IL-1β and tumor necrosis factor-alpha (TNF-α), and the release of TNF-α in a time-dependent manner. These findings show that Oα-Syn does not affect neurite outgrowth but induces a decrease in keratinocyte proliferation along with epidermal inflammation. With our tridimensional models, we demonstrated that the neurodegenerative protein Oα-Syn also degenerates the epidermis, drawing attention to the need of target-based screening to prevent and treat the effects of skin aging.

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