ICAMs in Immunity, Intercellular Adhesion and Communication.

Interactions among leukocytes and leukocytes with immune-associated auxiliary cells represent an essential feature of the immune response that requires the involvement of cell adhesion molecules (CAMs). In the immune system, CAMs include a wide range of members pertaining to different structural and functional families involved in cell development, activation, differentiation and migration. Among them, ß2 integrins (LFA-1, Mac-1, p150,95 and αDß2) are predominantly involved in homotypic and heterotypic leukocyte adhesion. ß2 integrins bind to intercellular (I)CAMs, actin cytoskeleton-linked receptors belonging to immunoglobulin superfamily (IgSF)-CAMs expressed by leukocytes and vascular endothelial cells, enabling leukocyte activation and transendothelial migration. ß2 integrins have long been viewed as the most important ICAMs partners, propagating intracellular signalling from ß2 integrin-ICAM adhesion receptor interaction. In this review, we present previous evidence from pioneering studies and more recent findings supporting an important role for ICAMs in signal transduction. We also discuss the contribution of immune ICAMs (ICAM-1, -2, and -3) to reciprocal cell signalling and function in processes in which ß2 integrins supposedly take the lead, paying particular attention to T cell activation, differentiation and migration.

Unraveling CD69 signaling pathways, ligands and laterally associated molecules.

CD69 is an early leukocyte activation marker involved in the regulation of the immune response. Initial in vitro studies evaluated its function using monoclonal antibodies until knock-out mice were developed. Subsequently, four ligands for CD69 have been identified, namely galectin-1, S100A8/S100A9 complex, myosin light chains 9 and 12, and oxidized low-density lipoproteins. In addition, several molecules are laterally associated with and regulated by CD69, including calreticulin and two transmembrane receptors, sphingosine-1-phosphate receptor (S1P1) and the heterodimeric amino acid transporter complex SLC7A5-SLC3A2 (LAT1-CD98). Recently, CD69 engagement has been shown to induce the expression of the immunoregulatory receptor programmed cell death-1 (PD-1) in T cells. The molecular signaling induced by CD69 has been explored in different scenarios and cell types. This review provides a perspective on the molecular pathways, ligands and cellular functions known to be regulated by CD69.

CD69 regula la expresión de PD-1 en linfocitos T CD4 / CD69 regulates PD-1 expression on CD4 T lymphocytes

D69 es una molécula inmunorreguladora que es expresada rápidamente por los leucocitos tras su activación, cuyo papel como inmunoregulador negativo, y no pro-inflamatorio, es cada vez más patente por las investigaciones in vivo que se están realizando. En el artículo publicado en Cell Mol Life Sci por María Jiménez como primera autora, se pone de manifiesto la capacidad de CD69 para unir y responder a lipoproteínas de baja densidad(LDL) aisladas y oxidadas in vitro (oxLDL). Esta unión incrementa la expresión de los receptores nucleares anti-inflamatorios NR4A, especialmente de NR4A3, y de PD1, molécula que actúa como freno para la activación de linfocitos T. Para ello, los autores han usado una línea estable de Jurkat que sobre-expresaCD69, linfocitos CD4 primarios, secuenciación masiva de ARNm, así como otras técnicas de biología molecular como el silenciamiento mediante ARN pequeño de interferencia para NR4A3,receptor nuclear que está implicado en la expresión de PD1. La unión de las oxLD La CD69 produjo el incremento de PD1 tanto a nivel de transcripción (ARNm) como de proteína (citometría deflujo). En este contexto, CD69 señaliza a través NFAT, un factor de transcripción dependiente de calcio. Por otra parte, los autores estudiaron biopsias de pacientes intervenidos por aneurisma de la aorta abdominal; en aquellos con inflamación crónica la expresión de PD1, NR4A3y CD69 está incrementada. Además, se observó una correlación positiva entre los niveles de ARNm de CD69 y de PD1 en estos pacientes, delos que más de la mitad presentaban hiperlipidemia. Estos datos apoyan el papel inmunoregulador negativo de CD69 en patologías como la aterosclerosis, y lo sitúan en el centro de rutas de señalización que actúan como freno de respuestas inflamatorias de origen inmunitario. (AU)

CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes.

The mechanisms that control the inflammatory-immune response play a key role in tissue remodelling in cardiovascular diseases. T cell activation receptor CD69 binds to oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflammation in atherosclerosis. To understand the downstream T cell responses triggered by the CD69-oxLDL binding, we incubated CD69-expressing Jurkat T cells with oxLDL. RNA sequencing revealed a differential gene expression profile dependent on the presence of CD69 and the degree of LDL oxidation. CD69-oxLDL binding induced the expression of NR4A receptors (NR4A1 and NR4A3), but also of PD-1. These results were confirmed using oxLDL and a monoclonal antibody against CD69 in CD69-expressing Jurkat and primary CD4 + lymphocytes. CD69-mediated induction of PD-1 and NR4A3 was dependent on NFAT activation. Silencing NR4A3 slightly increased PD-1 levels, suggesting a potential regulation of PD-1 by this receptor. Moreover, expression of PD-1, CD69 and NR4A3 was increased in human arteries with chronic inflammation compared to healthy controls, with a strong correlation between PD-1 and CD69 mRNA expression (r = 0.655 P < 0.0001). Moreover, PD-1 was expressed in areas enriched in CD3 infiltrating T cells. Our results underscore a novel mechanism of PD-1 induction independent of TCR signalling that might contribute to the role of CD69 in the modulation of inflammation and vascular remodelling in cardiovascular diseases.

Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis.

The interplay between T cells, dendritic cells and keratinocytes is crucial for the development and maintenance of inflammation in psoriasis. GADD45 proteins mediate DNA repair in different cells including keratinocytes. In the immune system, GADD45a and GADD45b regulate the function and activation of both T lymphocytes and dendritic cells and GADD45a links DNA repair and epigenetic regulation through its demethylase activity. Here, we analyzed the expression of GADD45a and GADD45b in the skin, dendritic cells and circulating T cells in a cohort of psoriasis patients and their regulation by inflammatory signals. Thirty patients (17 male/13 female) with plaque psoriasis and 15 controls subjects (7 male/8 female), were enrolled. Psoriasis patients exhibited a lower expression of GADD45a at the epidermis but a higher expression in dermal infiltrating T cells in lesional skin. The expression of GADD45a and GADD45b was also higher in peripheral T cells from psoriasis patients, although no differences were observed in p38 activation. The expression and methylation state of the GADD45a target UCHL1 were evaluated, revealing a hypermethylation of its promoter in lesional skin compared to controls. Furthermore, reduced levels of GADD45a correlated with a lower expression UCHL1 in lesional skin. We propose that the demethylase function of GADD45a may account for its pleiotropic effects, and the complex and heterogeneous pattern of expression observed in psoriatic disease.

A Differential Signature of Circulating miRNAs and Cytokines Between COVID-19 and Community-Acquired Pneumonia Uncovers Novel Physiopathological Mechanisms of COVID-19.

Coronavirus Disease 2019 (COVID-19) pneumonia is a life-threatening infectious disease, especially for elderly patients with multiple comorbidities. Despite enormous efforts to understand its underlying etiopathogenic mechanisms, most of them remain elusive. In this study, we compared differential plasma miRNAs and cytokines profiles between COVID-19 and other community-acquired pneumonias (CAP). A first screening and subsequent validation assays in an independent cohort of patients revealed a signature of 15 dysregulated miRNAs between COVID-19 and CAP patients. Additionally, multivariate analysis displayed a combination of 4 miRNAs (miR-106b-5p, miR-221-3p, miR-25-3p and miR-30a-5p) that significantly discriminated between both pathologies. Search for targets of these miRNAs, combined with plasma protein measurements, identified a differential cytokine signature between COVID-19 and CAP that included EGFR, CXCL12 and IL-10. Significant differences were also detected in plasma levels of CXCL12, IL-17, TIMP-2 and IL-21R between mild and severe COVID-19 patients. These findings provide new insights into the etiopathological mechanisms underlying COVID-19.

Expression of miR-135b in Psoriatic Skin and Its Association with Disease Improvement.

miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, the changes induced following the treatment with biologicals and their association with disease improvement. Next generation sequencing was performed from five skin samples from psoriasis patients (lesional and non-lesional skin) and five controls, and from this cohort, 12 microRNAs were selected to be analyzed in skin samples from 44 patients with plaque psoriasis. In 15 patients, an additional sample was obtained after three months of biological treatment. MiR-9-5p, miR-133a-3p and miR-375 were downregulated in the lesional skin of psoriasis patients. After treatment, expression of miR-133a-3p, miR-375, miR-378a and miR-135b in residual lesions returned towards the levels observed in non-lesional skin. The decrease in miR-135b levels after treatment with biologics was associated with both the improvement of patients evaluated through Psoriasis Area and Severity Index score and the decrease in local inflammatory response. Moreover, basal expression of miR-135b along with age was associated with the improvement of psoriasis, suggesting its possible usefulness as a prognostic biomarker.

Las redes sociales en la estrategia de implementación de evidencias en la práctica clínica: experiencia del Hospital Regional Universitario de Málaga, España / Social networks in the clinical practice evidence implementation strategy: experience from Hospital Regional Universitario de Málaga, Spain / Redes sociais na estratégia de implementação de evidências na prática clínica: experiência do Hospital Regional Universitario de Málaga, Espanha

Introducción. Twitter se ha convertido en el foro favorito para la comunicación de la atención médica, en cuanto permite a los usuarios publicar y compartir mensajes fácilmente a sus seguidores. En el Hospital Regional Universitario de Málaga (HRUM) se ha recurrido al uso de las redes sociales, particularmente Twitter, para facilitar la implementación y difusión de las recomendaciones de las Guías de Buenas Prácticas (GBP) de la Registered Nurses Association of Ontario (RNAO) en la práctica clínica. El objetivo del presente artículo es describir la estrategia y reflexionar acerca del rol de las redes sociales en las estrategias y los resultados de implantación de recomendaciones de GBP de la RNAO. Temas de reflexión. Siguiendo la metodología del modelo Best Practice Spotlight Organization (BPSO), se ha otorgado un papel protagonista a las enfermeras asistenciales de cada unidad a través de la formación, creación de equipos de implantación y difusión del programa. El uso de nuevos registros y, sobre todo, el uso de las redes sociales, ha obtenido unos resultados excelentes de adherencia de los profesionales al programa tanto a nivel cuantitativo como cualitativo. Conclusiones. El uso de las redes sociales como estrategia de difusión en la implantación de las recomendaciones de las GBP de la RNAO ha conseguido muy buena acogida por parte de los profesionales, pues muestra un alto nivel de participación, y es una herramienta útil como estrategia de difusión. Se necesita más tiempo para monitorizar el uso de las redes sociales y su posible impacto en la implantación de evidencias y la mejora de los resultados de salud de los pacientes y organizaciones de salud. Cómo citar: Bujalance Hoyos J, Grinspun D, Pérez Jiménez MT, Viñas Vera C, Jiménez Fernández MS, García Sánchez JA. Las redes sociales en la estrategia de implementación de evidencias en la práctica clínica: experiencia del Hospital Regional Universitario de Málaga, España. MedUNAB. 2020;23(1):107-117. doi:10.29375/01237047.3571

Introduction. Twitter has become the favored forum for communicating health care, since it allows users to publish and share messages with their followers. At Hospital Regional Universitario de Málaga (HRUM), they have used social networks, particularly Twitter, to facilitate implementing and broadcasting the recommendations from the Registered Nurses Association of Ontario's (RNAO) Best Practice Guideline (BPG) for clinical practice. The objective of this paper is to describe the strategy and reflect on the role of social networks on the strategies and results of implementing the RNAO's BPG recommendations. Topics of reflection. In accordance to the methodology of the Best Practice Spotlight Organization (BPSO) model, a leading role has been given to the nurses at each unit through training, creation of implementation teams and broadcasting the program. Using new records and, most of all, social networks, the strategy has obtained excellent results from professionals when it comes to adherence to the program, both quantitatively and qualitatively. Conclusions. The use of social networks as a broadcasting strategy in implementing the RNAO's BPG recommendations has been well received by professionals. The strategy shows high participation levels and is a useful tool as a broadcasting strategy. More time is needed to monitor social network use and its possible impact on generating evidence, as well as the improvement of healthcare organizations and patient's health results. Cómo citar: Bujalance Hoyos J, Grinspun D, Pérez Jiménez MT, Viñas Vera C, Jiménez Fernández MS, García Sánchez JA. Las redes sociales en la estrategia de implementación de evidencias en la práctica clínica: experiencia del Hospital Regional Universitario de Málaga, España. MedUNAB. 2020;23(1):107-117. doi:10.29375/01237047.3571

Introdução. O Twitter se tornou o fórum favorito para a comunicação no atendimento médico, pois permite que os usuários publiquem e compartilhem facilmente mensagens para seus seguidores. No Hospital Regional Universitário de Málaga (HRUM), foram utilizadas as redes sociais, particularmente o Twitter, para facilitar a implementação e disseminação das recomendações das Guias de Boas Práticas (GBP) da Registered Nurses Association of Ontario (RNAO) na prática clínica. O objetivo deste artigo é descrever a estratégia e refletir sobre o papel das redes sociais nas estratégias e nos resultados da implementação das recomendações do GBPs da RNAO. Tópicos de reflexão. Seguindo a metodología do modelo Best Practice Spotlight Organization, foi atribuído um papel essencial às enfermeiras de cada unidade por meio de treinamento, criação de equipes de implementação e divulgação do programa. O uso de novos registros e, sobretudo, o uso de redes sociais, obteve excelentes resultados de adesão dos profissionais ao programa, tanto quantitativa quanto qualitativamente. Conclusões. O uso das redes sociais como estratégia de disseminação na implementação das recomendações do GBPs da RNAO alcançou uma boa recepção pelos profissionais, pois mostra um alto nível de participação e é uma ferramenta útil como estratégia de disseminação. É necessário mais tempo para monitorar o uso das redes sociais e seu possível impacto na implementação de evidências e na melhoria dos resultados de saúde de pacientes e organizações de saúde. Cómo citar: Bujalance Hoyos J, Grinspun D, Pérez Jiménez MT, Viñas Vera C, Jiménez Fernández MS, García Sánchez JA. Las redes sociales en la estrategia de implementación de evidencias en la práctica clínica: experiencia del Hospital Regional Universitario de Málaga, España. MedUNAB. 2020;23(1):107-117. doi:10.29375/01237047.3571

Thrombospondin-1/CD47 Interaction Regulates Th17 and Treg Differentiation in Psoriasis.

Accumulating evidence on the role of Thrombospondin-1 (TSP-1) in the immune response has emerged during the last years. In spite of the importance of TSP-1 not only as anti-angiogenic factor but also as an immunomodulatory molecule, studies on the role of TSP-1 in psoriasis have been neglected. TSP-1 and CD47 expression were analyzed in skin samples from psoriasis patients and control subjects using RT-PCR and immunofluorescence. Expression of these molecules was also evaluated in peripheral blood CD4+ T cells, moDCs, and circulating primary DCs. The functional role of TSP-1/CD47 signaling axis in psoriasis was assessed in Th17 and Treg differentiation assays. Additionally, small interfering RNA assays specific to TSP-1 were performed in CD4+ T cells and monocyte derived DC to specifically evaluate the function of this protein. Lesional skin of psoriasis patients expressed lower TSP-1 and CD47 mRNA levels compared to non-lesional skin or skin from controls. Immunofluorescence staining revealed decreased expression of CD47 in CD45+ dermal cells from psoriasis samples compared to control subjects. Peripheral CD4+ T cells and circulating primary DCs from psoriasis also expressed lower levels of CD47 compared to controls. Although no significant differences were detected in TSP-1 expression in CD4+ T cells and moDCs between patients and controls, TSP-1 expression in psoriasis patients inversely correlated with disease activity evaluated by the Psoriasis Area and Index Activity. Furthermore, exogenous TSP-1 inhibited Th17 differentiation and stimulated the differentiation of CD4+ T cells toward Treg cells. Furthermore, RNA interference specific for TSP-1 confirmed the role of this molecule as a negative regulator of T cell activation. Because of the impact of TSP-1/CD47 signaling axis in Th17 and Treg differentiation, a dysregulated expression of these molecules in the immune cells from psoriasis patients may favor the exacerbated inflammatory response in this disease.