IL-10 deficiency exacerbates the brain inflammatory response to permanent ischemia without preventing resolution of the lesion

El pdf del artículo es la versión post-print.Stroke induces inflammation that can aggravate brain damage. This work examines whether interleukin-10 (IL-10) deficiency exacerbates inflammation and worsens the outcome of permanent middle cerebral artery occlusion (pMCAO). Expression of IL-10 and IL-10 receptor (IL-10R) increased after ischemia. From day 4, reactive astrocytes showed strong IL-10R immunoreactivity. Interleukin-10 knockout (IL-10 KO) mice kept in conventional housing showed more mortality after pMCAO than the wild type (WT). This effect was associated with the presence of signs of colitis in the IL-10 KO mice, suggesting that ongoing systemic inflammation was a confounding factor. In a pathogen-free environment, IL-10 deficiency slightly increased infarct volume and neurologic deficits. Induction of proinflammatory molecules in the IL-10 KO brain was similar to that in the WT 6 hours after ischemia, but was higher at day 4, while differences decreased at day 7. Deficiency of IL-10 promoted the presence of more mature phagocytic cells in the ischemic tissue, and enhanced the expression of M2 markers and the T-cell inhibitory molecule CTLA-4. These findings agree with a role of IL-10 in attenuating local inflammatory reactions, but do not support an essential function of IL-10 in lesion resolution. Upregulation of alternative immunosuppressive molecules after brain ischemia can compensate, at least in part, the absence of IL-10. © 2013 ISCBFM.Work supported by the Spanish Ministry of Economy (SAF2011-30492), and the European Community (FP7, grant agreements: n°201024 ARISE and n°278850 InMiND), and the ERANET-NEURON project (PRI-PIMNEU-2011-1342). IPP and EBT had PhD fellowships from the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) of the Generalitat de Catalunya and the FPU program of the Spanish Ministry of Economy, respectively.Peer Reviewe

Revista de educación

No podría valorarse correctamente la significación que tuvo la Escuela del... Magisterio en el contexto de las realizaciones pedagógicas españolas su olvidáramos el tiempo histórico que surgió no sólo su creación, sino su avatar a través de los años en que se desarrolló sus actividades docentes. Se creó a través de los decretos de 1909 y 11. Las líneas matrices del intento pedagógico que iba a llevarse a cabo estuvieron enraizadas en los planes del profesorado de los Estados Unidos y especialmente en las escuelas normales de Francia, pero carecía de la financiación de estas instituciones. En ella se formará la generalidad de los profesores de escuela normal e inspectores de enseñanza primaria En el transcurso de la vida docente de la Escuela Superior, se deseó vivamente convertirla en un centro pedagógico de amplios vuelos. A la postre, la frustración producida en este aspecto de su quehacer, contribuyó bastante a limitar sus posibilidades de supervivencia. Ofreció a través de todas sus promociones un ejemplo de camaradería y convivencia realmente admirables. Varias causas la hicieron posible: en primer lugar, los alumnos llegaban a la escuela con una madurez social envidiable, ya que todos eran por lo menos maestros, muchos maestros nacionales en activo; el número de alumnos era escaso y la identidad de fines les hacia confraternizar fácilmente; este compañerismo se fue acrecentando a través de todas las actividades extraescolares. Tan profundo fue este compañerismo, que hoy subsiste una Asociación de antiguos alumnos que se reúnen periódicamente para confirmar sus lazos de amistad.Ministerio Educación CIDEBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; [email protected]

Shaping Synapses by the Neural Extracellular Matrix

Accumulating data support the importance of interactions between pre- and postsynaptic neuronal elements with astroglial processes and extracellular matrix (ECM) for formation and plasticity of chemical synapses, and thus validate the concept of a tetrapartite synapse. Here we outline the major mechanisms driving: (i) synaptogenesis by secreted extracellular scaffolding molecules, like thrombospondins (TSPs), neuronal pentraxins (NPs) and cerebellins, which respectively promote presynaptic, postsynaptic differentiation or both; (ii) maturation of synapses via reelin and integrin ligands-mediated signaling; and (iii) regulation of synaptic plasticity by ECM-dependent control of induction and consolidation of new synaptic configurations. Particularly, we focused on potential importance of activity-dependent concerted activation of multiple extracellular proteases, such as ADAMTS4/5/15, MMP9 and neurotrypsin, for permissive and instructive events in synaptic remodeling through localized degradation of perisynaptic ECM and generation of proteolytic fragments as inducers of synaptic plasticity

Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia

Gemma Llovera et al.Numerous treatments have been reported to provide a beneficial outcome in experimental animal stroke models; however, these treatments (with the exception of tissue plasminogen activator) have failed in clinical trials. To improve the translation of treatment efficacy from bench to bedside, we have performed a preclinical randomized controlled multicenter trial (pRCT) to test a potential stroke therapy under circumstances closer to the design and rigor of a clinical randomized control trial. Anti-CD49d antibodies,which inhibit the migration of leukocytes into the brain, were previously investigated in experimental strokemodels by individual laboratories. Despite the conflicting results from four positive and one inconclusive preclinical studies, a clinical trial was initiated. To confirm the preclinical results and to test the feasibility of conducting a pRCT, six independent European research centers investigated the efficacy of anti-CD49d antibodies in two distinct mouse models of stroke in a centrally coordinated, randomized, and blinded approach. The results pooled from all research centers revealed that treatment with CD49d-specific antibodies significantly reduced both leukocyte invasion and infarct volume after the permanent distal occlusion of the middle cerebral artery, which causes a small cortical infarction. In contrast, anti-CD49d treatment did not reduce lesion size or affect leukocyte invasion after transient proximal occlusion of the middle cerebral artery, which induces large lesions. These results suggest that the benefits of immune-targeted approachesmay depend on infarct severity and localization. This study supports the feasibility of performing pRCTs.Peer Reviewe

Immature monocytes recruited to the ischemic mouse brain differentiate into macrophages with features of alternative activation

Acute stroke induces a local inflammatory reaction causing leukocyte infiltration. Circulating monocytes are recruited to the ischemic brain and become tissue macrophages morphologically indistinguishable from reactive microglia. However, monocytes are a heterogeneous population of cells with different functions. Herein, we investigated the infiltration and fate of the monocyte subsets in a mouse model of focal brain ischemia by permanent occlusion of the distal portion of the middle cerebral artery. We separated two main subtypes of CD11b monocytes according to their expression of the surface markers Ly6C and CD43. Using adoptive transfer of reporter monocytes and monocyte depletion, we identified the pro-inflammatory Ly6CCD43CCR2 subset as the predominant monocytes recruited to the ischemic tissue. Monocytes were seen in the leptomeninges from where they entered the cortex along the penetrating arterioles. Four days post-ischemia, they had invaded the infarcted core, where they were often located adjacent to blood vessels. At this time, Iba-1 and Iba-1 cells in the ischemic tissue incorporated BrdU, but BrdU incorporation was rare in the reporter monocytes. The monocyte phenotype progressively changed by down-regulating Ly6C, up-regulating F4/80, expressing low or intermediate levels of Iba-1, and developing macrophage morphology. Moreover, monocytes progressively acquired the expression of typical markers of alternatively activated macrophages, like arginase-1 and YM-1. Collectively, the results show that stroke mobilized immature pro-inflammatory Ly6CCD43 monocytes that acutely infiltrated the ischemic tissue reaching the core of the lesion. Monocytes differentiated to macrophages with features of alternative activation suggesting possible roles in tissue repair during the sub-acute phase of stroke.Financed by the Spanish Ministries of Economy MINECO (SAF2011-30492, SAF2014-56279) and Health (FIS PI12/01437), and the European Community FP7 (InMiND project n°278850). We acknowledge the Image and Cytometry platforms of IDIBAPS, and the Confocal Microscopy Unit of the Serveis Cientifico-Tècnics of the University of Barcelona for technical help. F.M.M. was supported by the ‘Red Invictus’ of the Instituto de Salud Carlos III (RD12/0014/0011).Peer Reviewe

Dynamycs of Proinflammatory Ly6Chi Monocytes with Immunosuppressive Features after Brain Ischemia in Mice

Comunicación presentada en el IX Simposi de Neurobiologia Experimental, celebrado los días 22 y 23 de octubre de 2014 en Barcelona y organizado por la Societat Catalana de Biologia del Institut d'Estudis CatalansWe investigated the responses of different monocyte subsets to stroke in a model of permanent middle cerebral artery occlusion in mice. Using strategies of adoptive transfer of reporter monocytes and monocyte depletion we show that stroke promotes the maturation of Ly6Chi monocytes to non-classic Ly6CloCD43hiCCR2- monocytes and stimulates the release of immature Ly6Chi from body reservoirs to the blood. Ly6Chi monocytes secreted cytokines after activation, showed high phagocytic activity, and were able to inhibit T cell proliferation, showing that they had proinflammatory but also direct immunosuppressive properties. The Ly6ChiCD43loCCR2+ cells were the predominant monocytes recruited to the ischemic tissue where they acquired features of macrophages over time. Acute pharmacologic CCR2 blockade reduced infarct volume showing that proinflammatory Ly6Chi monocyte infiltration in the acute phase of stroke is detrimental. However, stroke also increased Ly6Chi monocyte numbers in the spleen where the observed immunosuppressive features suggest they can control T cell reactivityPeer Reviewe

Neutrophil recruitment to the brain in mouse and human ischemic stroke

Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow–Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion. © 2014, Springer-Verlag Berlin HeidelbergSupported by the Spanish Ministries of Economy (SAF2011-30492) and Health (FIS PI12/01437), and FP7 EU projects ERANET-NEURON (PRI-PIMNEU-2011-1342) and InMIND (grant agreement no 278,850)Peer Reviewe