Bordetella pertussis infects the upper airways of humans and disarms host defense by the potent immuno-subversive activities of its pertussis (PT) and adenylate cyclase (CyaA) toxins. CyaA action near-instantly ablates the bactericidal activities of sentinel CR3-expressing myeloid phagocytes by hijacking cellular signaling pathways through the unregulated production of cAMP. Moreover, CyaA-elicited cAMP signaling also inhibits the macrophage colony-stimulating factor (M-CSF)-induced differentiation of incoming inflammatory monocytes into bactericidal macrophages. We show that CyaA/cAMP signaling via protein kinase A (PKA) downregulates the M-CSF-elicited expression of monocyte receptors for transferrin (CD71) and hemoglobin-haptoglobin (CD163), as well as the expression of heme oxygenase-1 (HO-1) involved in iron liberation from internalized heme. The impact of CyaA action on CD71 and CD163 levels in differentiating monocytes is largely alleviated by the histone deacetylase inhibitor trichostatin A (TSA), indicating that CyaA/cAMP signaling triggers epigenetic silencing of genes for micronutrient acquisition receptors. These results suggest a new mechanism by which B. pertussis evades host sentinel phagocytes to achieve proliferation on airway mucosa.IMPORTANCETo establish a productive infection of the nasopharyngeal mucosa and proliferate to sufficiently high numbers that trigger rhinitis and aerosol-mediated transmission, the pertussis agent Bordetella pertussis deploys several immunosuppressive protein toxins that compromise the sentinel functions of mucosa patrolling phagocytes. We show that cAMP signaling elicited by very low concentrations (22 pM) of Bordetella adenylate cyclase toxin downregulates the iron acquisition systems of CD14+ monocytes. The resulting iron deprivation of iron, a key micronutrient, then represents an additional aspect of CyaA toxin action involved in the inhibition of differentiation of monocytes into the enlarged bactericidal macrophage cells. This corroborates the newly discovered paradigm of host defense evasion mechanisms employed by bacterial pathogens, where manipulation of cellular cAMP levels blocks monocyte to macrophage transition and replenishment of exhausted phagocytes, thereby contributing to the formation of a safe niche for pathogen proliferation and dissemination.
- MeSH
- adenylátcyklasový toxin * metabolismus genetika MeSH
- AMP cyklický * metabolismus MeSH
- antigeny CD14 * metabolismus MeSH
- antigeny diferenciační myelomonocytární MeSH
- Bordetella pertussis * MeSH
- buněčná diferenciace * MeSH
- CD antigeny metabolismus genetika MeSH
- lidé MeSH
- monocyty * metabolismus imunologie mikrobiologie MeSH
- proteinkinasy závislé na cyklickém AMP metabolismus MeSH
- receptory buněčného povrchu metabolismus genetika MeSH
- signální transdukce * MeSH
- upregulace MeSH
- železo metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Sepsis has evolved as an enormous health issue amongst critically ill patients. It is a major risk factor that results in multiple organ failure and shock. Acute kidney injury (AKI) is one of the most frequent complications underlying sepsis, which portends a heavy burden of mortality and morbidity. Thus, the present review is aimed to provide an insight into the recent progression in the molecular mechanisms targeting dysregulated immune response and cellular dysfunction involved in the development of sepsis-associated AKI, accentuating the phytoconstituents as eligible candidates for attenuating the onset and progression of sepsis-associated AKI. The pathogenesis of sepsis-mediated AKI entails a complicated mechanism and is likely to involve a distinct constellation of hemodynamic, inflammatory, and immune mechanisms. Novel biomarkers like neutrophil gelatinase-associated lipocalin, soluble triggering receptor expressed on myeloid cells 1, procalcitonin, alpha-1-microglobulin, and presepsin can help in a more sensitive diagnosis of sepsis-associated AKI. Many bioactive compounds like curcumin, resveratrol, baicalin, quercetin, and polydatin are reported to play an important role in the prevention and management of sepsis-associated AKI by decreasing serum creatinine, blood urea nitrogen, cystatin C, lipid peroxidation, oxidative stress, IL-1β, TNF-α, NF-κB, and increasing the activity of antioxidant enzymes and level of PPARγ. The plant bioactive compounds could be developed into a drug-developing candidate in managing sepsis-mediated acute kidney injury after detailed follow-up studies. Lastly, the gut-kidney axis may be a more promising therapeutic target against the onset of septic AKI, but a deeper understanding of the molecular pathways is still required.
- MeSH
- akutní poškození ledvin * farmakoterapie etiologie diagnóza MeSH
- antigeny CD14 metabolismus MeSH
- biologické markery MeSH
- lidé MeSH
- lipokaliny terapeutické užití MeSH
- peptidové fragmenty metabolismus MeSH
- proteiny akutní fáze analýza metabolismus terapeutické užití MeSH
- sepse * komplikace farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Plaque-induced gingivitis is the most prevalent periodontal disease associated with pathogenic biofilms. The host immune system responds to pathogens through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and their co-receptor cluster of differentiation 14 (CD14). AIM: This study investigated the association between the functional polymorphism in the CD14 gene and the dental plaque microbiota in children with gingivitis. DESIGN: A total of 590 unrelated children (307 with plaque-induced gingivitis and 283 controls, aged 13-15 years) were enrolled in this case-control study. Dental plaque was processed using a ParoCheck® 20 detection kit. The CD14 -260C/T (rs2569190) polymorphism was determined with the PCR-RFLP method. RESULTS: Gingivitis was detected in 64.2% of boys and 35.8% of girls (P < .001). Children with gingivitis had a significantly higher occurrence of dental caries (P < .001). No significant differences in the CD14 -260C/T allele and genotype distribution among individuals with or without gingivitis in the whole cohort were found. Children with gingivitis and P gingivalis, however, were significantly more frequent carriers of the CT and TT genotypes than children with gingivitis without P gingivalis or healthy controls (P < .05). CONCLUSIONS: The CD14 -260C/T polymorphism acts in cooperation with P gingivalis to trigger plaque-induced gingivitis in Czech children.
- MeSH
- antigeny CD14 * MeSH
- dítě MeSH
- gingivitida * genetika MeSH
- lidé MeSH
- mladiství MeSH
- polymorfismus genetický MeSH
- Porphyromonas gingivalis MeSH
- studie případů a kontrol MeSH
- zubní kaz * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Plaque-induced gingivitis is the most prevalent periodontal disease associated with pathogenic biofilms. The host immune system responds to pathogens through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and their co-receptor cluster of differentiation 14 (CD14). AIM: This study investigated the association between the functional polymorphism in the CD14 gene and the dental plaque microbiota in children with gingivitis. DESIGN: A total of 590 unrelated children (307 with plaque-induced gingivitis and 283 controls, aged 13-15 years) were enrolled in this case-control study. Dental plaque was processed using a ParoCheck® 20 detection kit. The CD14 -260C/T (rs2569190) polymorphism was determined with the PCR-RFLP method. RESULTS: Gingivitis was detected in 64.2% of boys and 35.8% of girls (P < .001). Children with gingivitis had a significantly higher occurrence of dental caries (P < .001). No significant differences in the CD14 -260C/T allele and genotype distribution among individuals with or without gingivitis in the whole cohort were found. Children with gingivitis and P gingivalis, however, were significantly more frequent carriers of the CT and TT genotypes than children with gingivitis without P gingivalis or healthy controls (P < .05). CONCLUSIONS: The CD14 -260C/T polymorphism acts in cooperation with P gingivalis to trigger plaque-induced gingivitis in Czech children.
- MeSH
- antigeny CD14 * MeSH
- dítě MeSH
- gingivitida * genetika MeSH
- lidé MeSH
- mladiství MeSH
- polymorfismus genetický MeSH
- Porphyromonas gingivalis MeSH
- studie případů a kontrol MeSH
- zubní kaz * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Growing evidence suggests that diabetes mellitus is associated with impairment of the intestinal barrier. However, it is not clear so far if the impairment of the intestinal barrier is a consequence of prolonged hyperglycemia or the consequence of external factors influencing the gut microbiota and intestinal mucosa integrity. Aim of the study was to perform an estimation of relationship between serological markers of impairment of the intestinal barrier: intestinal fatty acid-binding protein (I-FABP), cytokeratin 18 caspase-cleaved fragment (cCK-18), and soluble CD14 (sCD14) and markers of prolonged hyperglycemia, such as the duration of diabetes mellitus and glycated hemoglobin (HbA1c) via a correlation analysis in patients with diabetes mellitus. In 40 adult patients with type 1 diabetes mellitus and 30 adult patients with type 2 diabetes mellitus the estimation has been performed. Statistically significant positive correlation was found between cCK-18 and HbA1c (r=0.5047, p=0.0275) in patients with type 1 diabetes mellitus with fading insulitis (T1D). In patients with type 1 diabetes mellitus with ongoing insulitis (T1D/INS) and in patients with type 2 diabetes mellitus (T2D), no statistically significant positive correlations were found between serological markers of intestinal barrier impairment (I-FABP, cCK-18, sCD14) and duration of diabetes or levels of HbA1c. Similarly, in cumulative cohort of patients with T1D/INS and patients with T1D we revealed statistically positive correlation only between HbA1c and cCK-18 (r=0.3414, p=0.0311). Surprisingly, we found statistically significant negative correlation between the duration of diabetes mellitus and cCK-18 (r=-0.3050, p=0.0313) only in cumulative group of diabetic patients (T1D, T1D/INS, and T2D). Based on our results, we hypothesize that the actual condition of the intestinal barrier in diabetic patients is much more dependent on variable interactions between host genetic factors, gut microbiota, and environmental factors rather than effects of long-standing hyperglycemia (assessed by duration of diabetes mellitus or HbA1c).
PURPOSE OF THE STUDY The aim of the study was to determine miR-146a-5p, miR-223-3p and miR-23a-3p by an enzyme immunoassay in patients with inflammatory and non-inflammatory joint effusion and to verify the usefulness of these miRNAs as biomarkers of joint inflammation. MATERIAL AND METHODS Synovial fluid (SF) samples were collected from 82 patients. The group consisted of 60 non-inflammatory, 11 inflammatory-non-pyogenic, 11 inflammatory-pyogenic SF. SF miRNA was isolated by RNA Isolation Kit Plasma/Serum. The concentrations of miRNA were determined by enzyme-linked immunosorbent assays (ELISA), C-reactive protein, interleukin-6 and procalcitonin on automatic analyser, presepsin on POCT system, interleukin-1 and human neutrofil defensins 1-3 by ELISA. RESULTS A statistically significant negative correlation was found between miR-146-5p and miR-223-3p, WBC, IL-1β, IL-6 and CRP (P < 0.05) in all groups; a statistically significant positive correlation was found between miR-223-3p and miR-23a-3p, WBC, PMN, IL-1beta, IL-6 and HNP1-3, as well as a positive correlation of miR-23a-3p with IL-1β, IL-6 and HNP1-3. A statistically significant difference was found between miR-146a-5p, miR-223-3p and miR-23a-3p and individual SF groups, P = 0.006, P < 0.001, respectively. PMN, WBC, Il-1β, IL-6, HNP 1-3 predicted the inflammatory processes with excellent diagnostic power (AUC > 0.9). The clinical relevance expressed by effect size was the strongest in miR-223-3p, PMN, IL-1 , HNP 1-3 between non-inflammatory and inflammatory-pyogenic group. CONCLUSIONS Our study quantified the SF miRNA by ELISA. We have shown that miR-146a-5p, miR-223-3p and miR-23a-3p can be an important group of biomarkers for the detection and monitoring of various pathophysiological conditions in synovial fluid, including inflammatory conditions. Key words: miRNA, synovial fluid, inflammatory joint disease, enzyme-linked immunosorbent assay.
- MeSH
- antigeny CD14 MeSH
- biologické markery MeSH
- lidé MeSH
- mikro RNA * genetika MeSH
- peptidové fragmenty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: The study aims were to verify the serum (S) and synovial fluid (SF) reference intervals (RIs) for human neutrophil defensins (HNP1-3); measure S and SF defensin concentrations in different types of SF, including non-inflammatory, inflammatory non-pyogenic, inflammatory pyogenic, and hemorrhagic; and to compare the HNP1-3 concentrations in SF and S with those of other inflammatory biomarkers. METHODS: SF and S samples were collected from 92 patients. HNP1-3 concentrations were determined using enzyme-linked immunosorbent assays; glucose, lactate, interleukin-6, and procalcitonin using an automatic analyzer; and presepsin using a Pathfast system. There were 61 non-inflammatory, 11 inflammatory non-pyogenic, 11 inflammatory pyogenic, and 9 hemorrhagic SF. Non-inflammatory SF was divided into non-inflammatory normal and non-inflammatory osteoarthritis. The former was used to estimate the HNP1-3 RI in SF and S. RESULTS: The estimated HNP1-3 RIs of SF and S were 12.47-437.42 mg/L and 5.45-44.75 μg/L, respectively. HNP1-3 differed significantly between S and SF and individual groups of SF (P<0.001 and P=0.001, respectively). There were significant relationships between SF HNP1-3 and S HNP1-3 (P<0.001), S C-reactive protein (P<0.001), and S interleukin-6 (P=0.007), and between SF HNP1-3 and SF C-reactive protein (P=0.004) and SF interleukin-6 (P<0.001). The highest kappa coefficient was between SF HNP1-3 and SF interleukin-6 (κ=0.507). CONCLUSIONS: We validated the SF HNP1-3 diagnostic kit and demonstrated that SF and S HNP1-3 are promising biomarkers for distinguishing inflammatory from non-inflammatory joint diseases.
- MeSH
- alfa-defensiny * MeSH
- antigeny CD14 MeSH
- biologické markery MeSH
- C-reaktivní protein MeSH
- ELISA * MeSH
- interleukin-6 MeSH
- lidé MeSH
- peptidové fragmenty MeSH
- synoviální tekutina MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Blood monocyte subsets are emerging as biomarkers of cardiovascular inflammation. However, our understanding of human monocyte heterogeneity and their immunophenotypic features under healthy and inflammatory conditions is still evolving. RATIONALE: In this study, we sought to investigate the immunophenome of circulating human monocyte subsets. METHODS: Multiplexed, high-throughput flow cytometry screening arrays and computational data analysis were used to analyze the expression and hierarchical relationships of 242 specific surface markers on circulating classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocytes in healthy adults. RESULTS: Using generalized linear models and hierarchical cluster analysis, we selected and clustered epitopes that most reliably differentiate between monocyte subsets. We validated existing transcriptional profiling data and revealed potential new surface markers that uniquely define the classical (e.g., BLTR1, CD35, CD38, CD49e, CD89, CD96), intermediate (e.g., CD39, CD275, CD305, CDw328), and nonclassical (e.g., CD29, CD132) subsets. In addition, our analysis revealed phenotypic cell clusters, identified by dendritic markers CMRF-44 and CMRF-56, independent of the traditional monocyte classification. CONCLUSION: These results reveal an advancement of the clinically applicable multiplexed screening arrays that may facilitate monocyte subset characterization and cytometry-based biomarker selection in various inflammatory disorders.
- MeSH
- antigeny CD14 metabolismus MeSH
- ateroskleróza diagnóza imunologie MeSH
- biodiverzita MeSH
- biologické markery metabolismus MeSH
- fenotyp MeSH
- imunofenotypizace metody MeSH
- krevní oběh MeSH
- lidé MeSH
- monocyty fyziologie MeSH
- průtoková cytometrie MeSH
- receptory IgG metabolismus MeSH
- rychlé screeningové testy MeSH
- separace buněk MeSH
- shluková analýza MeSH
- zánět diagnóza imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antigeny CD14 analýza MeSH
- biologické markery analýza MeSH
- C-reaktivní protein analýza MeSH
- interleukin-6 analýza MeSH
- kultivační vyšetření krve metody MeSH
- leukocytární L1-antigenní komplex analýza MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecká sepse * diagnóza MeSH
- prokalcitonin analýza MeSH
- receptory IgG analýza MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
Objective: In recent years, the role of the modern inflammatory markers TREM-1 (triggering receptors expressed on myeloid cells) and HMGB1 (high mobility group box 1 protein) in tumorigenesis has begun to be studied. Their role in gliomas is not clear. The aim of our study was to find the role of inflammation in gliomas. Patients and Methods. In 63 adult patients with gliomas and 31 healthy controls, the expressions of TREM-1 and TREM-2 on CD14+ blood cells (method: flow cytometry) and the levels of soluble sTREM-1, HMGB1, IL-6, and IL-10 (Elisa tests) were analyzed. Results: Cox proportional hazard analysis showed that a TREM-1/TREM-2 ratio was associated with reduced overall survival (HR = 1.001, P = 0.023). Patients with a TREM-1/TREM-2 ratio above 125 survived significantly shorter than patients with a TREM-1/TREM-2 ratio below 125. The percentage of CD14+ TREM-1+ cells was strongly associated with a plasma IL-6/IL-10 ratio (positively) and with IL-10 (negatively). Conversely, we found a higher percentage of CD14+ TREM-2+ monocytes in better surviving patients; these cells could downregulate the exaggerated inflammation and potentiate the phagocytosis in the tumor. The serum levels of HMGB1 negatively correlated with the percentage of CD14+ TREM-1+ cells and with the TREM-1/TREM-2 ratio. The positive correlation between the serum levels of a late proinflammatory cytokine HMGB1 with the percentage of TREM2+ CD14+ monocytes can be explained as an effort for suppression of systemic inflammation by anti-inflammatory acting CD14+ TREM-2+ cells. Conclusion: We showed that the TREM-1/TREM-2 ratio (expression on the surface of blood monocytes) could help predict prognosis in patients with gliomas, especially in high-grade gliomas, and that systemic inflammation has an impact on the patient's overall survival. This is the first study that showed that TREM expression on monocytes in peripheral blood could help predict prognosis in patients with gliomas.
- MeSH
- antigeny CD14 metabolismus MeSH
- dospělí MeSH
- gliom krev metabolismus mortalita MeSH
- interleukin-10 krev MeSH
- interleukin-6 krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové glykoproteiny metabolismus MeSH
- monocyty metabolismus MeSH
- proporcionální rizikové modely MeSH
- protein HMGB1 krev MeSH
- receptor TREM-1 metabolismus MeSH
- receptory imunologické metabolismus MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
