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The incidence of age-related dementia is growing with increased longevity, yet there are currently no disease-modifying therapies for these devastating disorders. Studies over the last several years have led to an evolving awareness of the role of the immune system in supporting brain maintenance and repair, displaying a diverse repertoire of functions while orchestrating the crosstalk between the periphery and the brain. Here, we provide insights into the current understanding of therapeutic targets that could be adopted to modulate immune cell fate, either systemically or locally, to defeat brain aging and neurodegeneration.

Tesis (Doctor en Ciencias Químicas) - - Universidad Nacional de Córdoba. Facultad de Ciencias Químicas, 2018. IMPACTO DE LA INFLAMACiÓN SISTÉMICA EN LA RESPUESTA INMUNE DEL SISTEMA NERVIOSO CENTRAL La microglía residente y los leucocitos periféricos tienen un rol esencial influenciando la respuesta inmune en el sistema nervioso central (SNC). Estas células se activan y migran en respuesta a quimiocinas producidas durante respuestas inmunes activas, pudiendo contribuir a la progresión de la neuroinflamación. El reciente hallazgo de agregados de proteína alfa-sinucleína (a-SYN) mal plegada que amplifican de forma similar a los priones, ha llevado a la hipótesis de que el sistema inmune podría estar participando en la propagación de a-SYN en sinucleinopatías como la enfermedad de Parkinson (PD). En este trabajo de tesis, evaluamos la participación de los interferones (IFNs) de tipo I y " en la respuesta ejercida por la microglía y los monocitos inflamatorios para de esta forma, comprender la contribución de estas citocinas en el establecimiento y desarrollo de un proceso neuroinflamatorio. Además, determinamos el impacto de la inflamación sistémica en la diseminación de a-SYN para comprender el rol de la microglía y los monocitos inflamatorios en la progresión del PD. . Luego del desafío sistémico con lipopolisacárido (LPS), encontramos reactividad glial junto con un activo reclutamiento de leucocitos en órganos circunventriculares, próximo a células vasculares endoteliales. A diferencia de la microglía, los monocitos inflamatorios pre-activados con LPS y purificados de cerebro fueron capaces de inducir la proliferación de células T. Además, su re-estimulación ex vivo con LPS promovió la exacerbación de la respuesta proliferativa T. Estas células mieloides, al contrario de los neutrófilos, demostraron también ser reclutadas de manera dependiente de los IFNs de tipo 1,revelando un rol para estas citocinas en su migración al SNC. En un modelo patológico, a-SYN administrada sistémicamente, fue internalizada preferentemente por monocitos Página 19 Página 110 RESUMEN 1 Javier M. Peralta Ramos inflamatorios pre-activados con LPS, respuesta que favoreció su diseminación en cerebro y médula espina!. En síntesis, nuestros resultados comparan las características funcionales y fenotípicas entre células residentes vs. reclutadas periféricas en un microambiente inflamatorio, identificando a los monocitos inflamatorios como un tipo celular clave en un modelo de neuroinflamación inducido por la administración sistémica con LPS y como potenciales células carrier que participarían en la diseminación de a-SYN en el desarrollo' del PD. Etiquetas de esta biblioteca: No hay etiquetas de esta biblioteca para este título. 2020-12-31 Peralta Ramos, Javier María. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina. Iribarren, Pablo. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Scimonelli, Teresa Nieves. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Lopez, Pablo Héctor Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Morón, Víctor Gabriel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Ramos, Alberto Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología Celular y Neurociencia Prof. Eduardo E. De Robertis; Argentina.

Additional file 4 Supplementary Fig. 3. WT spleens show changes in CD4+ T cell populations following anti-PD-L1 antibody treatment. WT mice were i.p. injected with αPD-L1 (or IgG), and spleens were collected 3 and 7 days after the treatment and analyzed by multiparametric flow cytometry. (A) Flow cytometry analyses of Tregs (One-way ANOVA F(2,15) = 7.697, **p = 0.005. Post-hoc uncorrected Fisher’s LSD multiple comparisons between αPD-L1 and IgG groups: *p

Additional file 3 Supplementary Fig. 2. Hippocampal human tau pS199 levels are reduced following anti-PD-L1 antibody treatment. αPD-L1 or IgG were i.p. injected to DM-hTAU mice. Hippocampi were analyzed for human tau pS199 levels 1 month afterwards. Untreated WT mice served as healthy controls. The graph shows hippocampal human tau protein pS199 amounts (pg) that were measured by ELISA and were normalized to the amount of total protein in each tissue (μg). One-way ANOVA F(2,15) = 135.2, ***p

Additional file 1 Supplementary Table 1. Antibodies used in CyTOF experiments.

Additional file 4 Supplementary Fig. 3. WT spleens show changes in CD4+ T cell populations following anti-PD-L1 antibody treatment. WT mice were i.p. injected with αPD-L1 (or IgG), and spleens were collected 3 and 7 days after the treatment and analyzed by multiparametric flow cytometry. (A) Flow cytometry analyses of Tregs (One-way ANOVA F(2,15) = 7.697, **p = 0.005. Post-hoc uncorrected Fisher’s LSD multiple comparisons between αPD-L1 and IgG groups: *p

Additional file 6 Supplementary Table 2. The ratio between the number of cells found in the brain following co-administration of αCCR2 and αPD-L1 relative to administration of αPD-L1 alone, was similar for both monocytes and Tregs.

Additional file 6 Supplementary Table 2. The ratio between the number of cells found in the brain following co-administration of αCCR2 and αPD-L1 relative to administration of αPD-L1 alone, was similar for both monocytes and Tregs.

Additional file 3 Supplementary Fig. 2. Hippocampal human tau pS199 levels are reduced following anti-PD-L1 antibody treatment. αPD-L1 or IgG were i.p. injected to DM-hTAU mice. Hippocampi were analyzed for human tau pS199 levels 1 month afterwards. Untreated WT mice served as healthy controls. The graph shows hippocampal human tau protein pS199 amounts (pg) that were measured by ELISA and were normalized to the amount of total protein in each tissue (μg). One-way ANOVA F(2,15) = 135.2, ***p

Additional file 5 Supplementary Fig. 4. Anti-CCR2 antibody induces reduction in brain infiltrating monocytes following anti-PD-L1 antibody treatment. This experiment included three groups of DM-hTAU mice treated either with: IgG, αPD-L1 or αCCR2 + αPD-L1. αCCR2 was i.p. injected to DM-hTAU mice 3 days prior (Day − 3) to αPD-L1 (Day 0), and then again on days 1, 5 and 9. The brains were analyzed by multiparametric flow cytometry 3 days after the last αCCR2 injection (Day 12). (A) Flow cytometry gating strategy, and (B) quantification of infiltrating monocytes in the brain of DM-hTAU mice. One-way ANOVA F(2,15) = 3.591, p = 0.0532. Post-hoc uncorrected Fisher’s LSD multiple comparisons between the groups: *p

Additional file 5 Supplementary Fig. 4. Anti-CCR2 antibody induces reduction in brain infiltrating monocytes following anti-PD-L1 antibody treatment. This experiment included three groups of DM-hTAU mice treated either with: IgG, αPD-L1 or αCCR2 + αPD-L1. αCCR2 was i.p. injected to DM-hTAU mice 3 days prior (Day − 3) to αPD-L1 (Day 0), and then again on days 1, 5 and 9. The brains were analyzed by multiparametric flow cytometry 3 days after the last αCCR2 injection (Day 12). (A) Flow cytometry gating strategy, and (B) quantification of infiltrating monocytes in the brain of DM-hTAU mice. One-way ANOVA F(2,15) = 3.591, p = 0.0532. Post-hoc uncorrected Fisher’s LSD multiple comparisons between the groups: *p

Additional file 2 Supplementary Fig. 1. Lack of changes in general locomotor activity following anti-PD-L1 antibody or anti-CCR2 antibody injections. This experiment included four groups of DM-hTAU mice treated either with: IgG, αPD-L1, αCCR2 + αPD-L1, or αCCR2. An additional group of WT mice served as healthy controls. αCCR2 was i.p. injected to DM-hTAU mice 3 days prior (Day − 3) to αPD-L1 or IgG (Day 0), and again on days 1, 5 and 9. The graph shows locomotor activity of females measured during the habituation trial in the novel object recognition test assessed 1 month after αPD-L1 treatment. n = 3–8 mice per group. Data are presented as mean ± s.e.m.

Additional file 1 Supplementary Table 1. Antibodies used in CyTOF experiments.

Additional file 2 Supplementary Fig. 1. Lack of changes in general locomotor activity following anti-PD-L1 antibody or anti-CCR2 antibody injections. This experiment included four groups of DM-hTAU mice treated either with: IgG, αPD-L1, αCCR2 + αPD-L1, or αCCR2. An additional group of WT mice served as healthy controls. αCCR2 was i.p. injected to DM-hTAU mice 3 days prior (Day − 3) to αPD-L1 or IgG (Day 0), and again on days 1, 5 and 9. The graph shows locomotor activity of females measured during the habituation trial in the novel object recognition test assessed 1 month after αPD-L1 treatment. n = 3–8 mice per group. Data are presented as mean ± s.e.m.