Dysregulation in CD39/CD73 Axis May Trigger the Upsurge of the Immune Suppressive Agent Adenosine in OSA Patients

Introduction Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Interestingly, adenosinergic signaling has emerged as a powerful immune checkpoint driving tumor development and progression. Methods Here, we explored the expression of the adenosinergic ecto-enzymes CD39 and CD73 in T-lymphocytes of OSA patients without any evidence of cancer, as well as their soluble forms in plasma (sCD39 and sCD73), along with adenosine. In addition, we explored the role of intermittent hypoxia (IH) in this context by in vitro models. Results Our results showed that CD39 is upregulated while CD73 is downregulated in OSA T-cells’ membrane. Moreover, our findings suggest that IH, through HIF-1, mediates the upregulation of both CD39 and CD73; and that CD73 downregulation could be mediated by a higher release of sCD73 by OSA T-lymphocytes. Importantly, we found that both sCD39 and sCD73 are upregulated in OSA plasma, suggesting T-lymphocytes as a potential source for plasmatic sCD73. Finally, our data propose the alterations in CD39/CD73 axis could underlie the upsurge of adenosine levels in the plasma of OSA patients. Conclusion Our study reveals a hypoxia-mediated alteration of the CD39/CD73 axis in OSA patients, which could trigger ADO upregulation, thus potentially contributing to the immune suppressive environment and ultimately facilitating tumor development and progression. Therefore, our data highlights the need for new longitudinal studies evaluating CD39 and/or CD73 as potential cancer-risk prognostic biomarkers in OSA patients. (AU)

Dysregulation in CD39/CD73 Axis May Trigger the Upsurge of the Immune Suppressive Agent Adenosine in OSA Patients.

INTRODUCTION: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Interestingly, adenosinergic signaling has emerged as a powerful immune checkpoint driving tumor development and progression. METHODS: Here, we explored the expression of the adenosinergic ecto-enzymes CD39 and CD73 in T-lymphocytes of OSA patients without any evidence of cancer, as well as their soluble forms in plasma (sCD39 and sCD73), along with adenosine. In addition, we explored the role of intermittent hypoxia (IH) in this context by in vitro models. RESULTS: Our results showed that CD39 is upregulated while CD73 is downregulated in OSA T-cells' membrane. Moreover, our findings suggest that IH, through HIF-1, mediates the upregulation of both CD39 and CD73; and that CD73 downregulation could be mediated by a higher release of sCD73 by OSA T-lymphocytes. Importantly, we found that both sCD39 and sCD73 are upregulated in OSA plasma, suggesting T-lymphocytes as a potential source for plasmatic sCD73. Finally, our data propose the alterations in CD39/CD73 axis could underlie the upsurge of adenosine levels in the plasma of OSA patients. CONCLUSION: Our study reveals a hypoxia-mediated alteration of the CD39/CD73 axis in OSA patients, which could trigger ADO upregulation, thus potentially contributing to the immune suppressive environment and ultimately facilitating tumor development and progression. Therefore, our data highlights the need for new longitudinal studies evaluating CD39 and/or CD73 as potential cancer-risk prognostic biomarkers in OSA patients.

SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells.

BACKGROUND: Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. METHODS: In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. RESULTS: S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1ß formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1ß. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. CONCLUSION: S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.

PSGL-1: a novel immune checkpoint driving T-cell dysfunction in obstructive sleep apnea.

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy. Methods: The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models. Results: Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia. Discussion: In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.

Relación entre factores meteorológicos y número y gravedad de crisis asmáticas atendidas en urgencias / Association between meteorological factors and frequency and severity of asthma exacerbations attended in the pediatric emergency room

Introducción: la influencia del clima en las exacerbaciones asmáticas ha sido demostrada, pero los estudios que analizan la relación de los diferentes factores meteorológicos con la crisis asmática en Pediatría son limitados. El objetivo de este estudio es analizar la relación entre varios factores meteorológicos y las crisis asmáticas en una población pediátrica de un hospital de tercer nivel situado en una región con clima oceánico. Material y métodos: estudio descriptivo retrospectivo de los pacientes de 1 a 16 años atendidos en urgencias por crisis asmática, durante un periodo de cinco años. Se recogió la edad, el sexo y la necesidad de ingreso hospitalario. Las variables meteorológicas (velocidad del viento, precipitaciones, radiación solar, temperatura, humedad relativa y presión barométrica) se obtuvieron del Centro de Investigación del Medio Ambiente (CIMA). Se analizó mediante regresión logística la relación de las variables meteorológicas con el número de visitas a urgencias y el porcentaje de ingresos por crisis asmática. Resultados: se identificaron 8534 visitas a urgencias por crisis asmática, con un pico de incidencia en septiembre. Se obtuvo una relación inversa estadísticamente significativa de la radiación solar y las precipitaciones con el número de visitas a urgencias y el porcentaje de ingresos. Conclusiones: este estudio, realizado en una región de clima oceánico, confirma el patrón estacional ya descrito previamente para las exacerbaciones asmáticas. Se evidencia asociación inversa estadísticamente significativa entre las precipitaciones y la radiación solar con el número de visitas a urgencias y el porcentaje de ingresos por crisis asmáticas (AU)

Object: the influence of climate on asthma exacerbations has already been demonstrated but the studies that analyze the association between different meteorological factors and acute asthma exacerbation in pediatric patients are limited. The aim of the present study is determining association between some meteorological conditions and asthma exacerbations in children in a third level referral Academic Hospital located in an oceanic-climate area.Methods: we conducted a descriptive and retrospective study in 1 to 16 years old patients presenting with an asthma attack in the emergency department, during a 5-year period. Data about age, sex and the need for hospital admission were collected. Meteorological data (wind speed, rain, sunlight, temperature, humidity and barometric pressure) were obtained from the Environmental Research Center. The number of emergency department visits and percentage of hospital admissions were correlated to meteorological factors using logistic regression analysis.Results: a total of 8534 asthma exacerbations were attended in the emergency department with a peak incidence in September. It was found that sunlight and rain were significantly and inversely correlated with emergency department visits and percentage of hospital admissions.Conclusions: this study, conducted in an oceanic-climate area, confirms the previously described seasonal pattern for asthma exacerbations. We probe a statistically significant and inverse correlation between rain and sunlight and the number of emergency department visits for asthma and percentage of hospital admissions due to asthma attack. (AU)

SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-ß) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-ß pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.