A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection. Neutrophils display circadian oscillations in numbers and phenotype in the circulation. Adrover and colleagues now identify the molecular regulators of neutrophil aging and show that genetic disruption of this process has major consequences in immune cell trafficking, anti-microbial defense, and vascular health.This study was supported by Intramural grants from A∗STAR to L.G.N., BES-2013-065550 to J.M.A., BES-2010-032828 to M.C.-A, and JCI-2012-14147 to L.A.W (all from Ministerio de Economía, Industria y Competitividad; MEIC). Additional MEIC grants were SAF2014-61993-EXP to C.L.-R.; SAF2015-68632-R to M.A.M. and SAF-2013-42920R and SAF2016-79040Rto D.S. D.S. also received 635122-PROCROP H2020 from the European Commission and ERC CoG 725091 from the European Research Council (ERC). ERC AdG 692511 PROVASC from the ERC and SFB1123-A1 from the Deutsche Forschungsgemeinschaft were given to C.W.; MHA VD1.2/81Z1600212 from the German Center for Cardiovascular Research (DZHK) was given to C.W. and O.S.; SFB1123-A6 was given to O.S.; SFB914-B08 was given to O.S. and C.W.; and INST 211/604-2, ZA 428/12-1, and ZA 428/13-1 were given to A.Z. This study was also supported by PI12/00494 from Fondo de Investigaciones Sanitarias (FIS) to C.M.; PI13/01979, Cardiovascular Network grant RD 12/0042/0054, and CIBERCV to B.I.; SAF2015-65607-R, SAF2013-49662-EXP, and PCIN-2014-103 from MEIC; and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) to A.H. The CNIC is supported by the MEIC and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505)

Biologic Disease-modifying antirheumatic drug attributes in the first lines of treatment of rheumatoid arthritis. 2015 ACORDAR project

Existen pacientes con artritis reumatoide (AR) que no responden de la forma deseada a la terapia biológica. Nuestro objetivo fue reconocer los atributos del FAME biológico (FAMEb) que podrían identificar al más adecuado en las primeras líneas de tratamiento de la AR. Métodos Para reconocer los atributos que podrían definir el FAMEb, se realizó una búsqueda sistemática de la literatura acerca de aspectos generales, farmacología, eficacia, seguridad, administración y coste. A continuación, se realizó un proceso Delphi a 2 rondas entre un grupo de reumatólogos expertos en el manejo de la AR para determinar el grado de acuerdo con los atributos identificados, indicando el grado de importancia que se le daba a cada atributo. Se aplicaron 2 criterios para determinar la consistencia de los resultados: 1) sobre la base de la mediana y el rango intercuartílico, y 2) el cumplimiento simultáneo de media, mediana, desviación estándar, rango intercuartílico y coeficiente de variación. Se determinaron también la concordancia y la ratificación final del panel de expertos. Resultados Ochenta y tres reumatólogos españoles completaron las 2 circulaciones del proceso Delphi. Ninguno de los 77 atributos identificados se consideró de baja importancia, 75 de los 77 (97,4%) se consideraron de alta importancia y 76 de los 77 (98,7%) fueron ratificados. Quince tuvieron el apoyo del 100% del grupo de trabajo. Conclusiones Quince atributos tuvieron el apoyo del 100% del grupo de trabajo y podrían considerarse los que definirían el FAMEb ideal en las primeras líneas de tratamiento de la AR.To date, between 17% and 35% of patients with rheumatoid arthritis (RA) do not respond as expected to the initial biological therapy. The objective of this project is to recognize and weigh the attributes of biologic DMARD (bDMARD) to identify the most appropriate for each case, in the first lines of treatment of RA (after inadequate response to at least one synthetic DMARD or previous bDMARD). Methods To recognize the possible attributes that could define the bDMARD, we performed a systematic search of the literature that recognized the possible attributes involving general aspects, pharmacology, efficacy, safety, management, and cost. Then a Delphi process was conducted with two rounds among a group of selected expert rheumatologists in the management of RA indicating the degree of agreement with the attributes identified in the literature. The project was completed between February and September 2015, indicating the degree of importance that was ascribed to each attribute. Two criteria were applied to determine the consistency of results: 1) based on the median and interquartile range; and 2) on the simultaneous compliance with mean, median, standard deviation, interquartile range and coefficient of variation. The agreement and final ratification of the expert panel were also determined. Results Eighty-three Spanish rheumatologists participated and completed both rounds of the Delphi process. In no case was the importance of the 77 attributes identified considered to be low; 75 of 77 (97.4%) were considered highly important and 76 of 77 (98.7%) were ratified. Fifteen attributes had the support of 100% of the working group. Conclusions There was a high degree of agreement concerning the selected attributes. Fifteen of them had the support of 100% of the working group and could be considered the definition of the ideal bDMARD in the first lines of RA treatment.Sin financiaciónNo data JCR 20180.363 SJR (2018) Q3, 38/66 RheumatologyNo data IDR 2018UE