The dual effect of acetate on microglial TNF-α production

Introduction: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. Objective: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. Method: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Results: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Conclusion: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

Obligatory intracellular parasites such as Plasmodium sp, Trypanosoma cruzi, Toxoplasma gondii and Leishmania sp are responsible for the infection of hundreds of millions of individuals every year. These parasites can deliver antigens to the host cell cytoplasm that are presented through MHC class I molecules to protective CD8 T cells. The in vivo priming conditions of specific CD8 T cells during natural infection are largely unknown and remain as an area that has been poorly explored. The antiparasitic mechanisms mediated by CD8 T cells include both interferon-g-dependent and -independent pathways. The fact that CD8 T cells are potent inhibitors of parasitic development prompted many investigators to explore whether induction of these T cells can be a feasible strategy for the development of effective subunit vaccines against these parasitic diseases. Studies performed on experimental models supported the hypothesis that CD8 T cells induced by recombinant viral vectors or DNA vaccines could serve as the basis for human vaccination. Regimens of immunization consisting of two different vectors (heterologous prime-boost) are much more efficient in terms of expansion of protective CD8 T lymphocytes than immunization with a single vector. The results obtained using experimental models have led to clinical vaccination trials that are currently underway.Parasitas intracelulares obrigatórios como Plasmodium sp, Trypanosoma cruzi, Toxoplasma gondii e Leishmania sp são responsáveis pela infecção de milhões de indivíduos a cada ano. Estes parasitas são capazes de liberar antígenos no citoplasma de células infectadas do hospedeiro que são apresentados por moléculas de MHC classe I para células T CD8 protetoras. As condições de estímulo in vivo destas células T CD8 específicas durante a infecção natural são pouco conhecidas e constituem uma área pouco explorada. Os mecanismos anti-parasitários mediados por células T CD8 incluem vias dependentes e independentes do interferon-g. O fato que células T CD8 são potentes inibidores do desenvolvimento parasitário levou diversos investigadores a explorarem se a indução destes linfócitos T poderia constituir uma estratégia factível para o desenvolvimento de vacinas efetivas contra estas doenças parasitárias. Estudos feitos em modelos experimentais suportam a hipótese que células T CD8 induzidas por vetores recombinantes virais ou vacinas de DNA podem servir de base para a vacinação humana. Regimes de imunização consistindo de dois vetores distintos (prime-boost heterólogo) são muito mais eficientes em termos da expansão de linfócitos T CD8 protetores do que a imunização com um único vetor. Os resultados obtidos usando modelos experimentais levaram a vacinações clínicas que estão atualmente em curso.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Microbiologia, Imunologia e ParasitologiaUniversidade de São Paulo Faculdade de Ciências Farmacêuticas Departamento de Análises Clínicas e ToxicológicasUNIFESP, EPM, Depto. de Microbiologia, Imunologia e ParasitologiaSciEL

Leukotrienes Produced in Allergic Lung Inflammation Activate Alveolar Macrophages

It has been well-documented that leukotrienes (LTs) are released in allergic lung inflammation and that they participate in the physiopathology of asthma. A role for LTs in innate immunity has recently emerged: Cys-LTs were shown to enhance Fc gamma R-mediated phagocytosis by alveolar macrophages (AMs). Thus, using a rat model of asthma, we evaluated Fc gamma R-mediated phagocytosis and killing of Klebsiella pneumoniae by AMs. the effect of treatment with a cys-LT antagonist (montelukast) on macrophage function was also investigated. Male Wistar rats were immunized twice with OVA/alumen intraperitoneally and challenged with OVA aerosol. After 24 h, the animals were killed, and the AMs were obtained by bronchoalveolar lavage. Macrophages were cultured with IgG-opsonized red blood cells (50: 1) or IgG-opsonized K. pneumoniae (30: 1), and phagocytosis or killing was evaluated. Leukotriene C(4) and nitric oxide were quantified by the EIA and Griess methods, respectively. the results showed that AMs from sensitized and challenged rats presented a markedly increased phagocytic capacity via Fc gamma R (10X compared to controls) and enhanced killing of K. pneumoniae (4X higher than controls). the increased phagocytosis was inhibited 15X and killing 3X by treatment of the rats with montelukast, as compared to the non-treated group. cys-LT addition increased phagocytosis in control AMs but had no effect on macrophages from allergic lungs. Montelukast reduced nitric oxide (39%) and LTC(4) (73%). These results suggest that LTs produced during allergic lung inflammation potentiate the capacity of AMs to phagocytose and kill K. pneumonia via Fc gamma R. Copyright (C) 2010 S. Karger AG, BaselConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Complex Fluids INCTFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Disciplina Nefrol, Dept Nefrol, Lab Imunol Clin & Expt, BR-04023900 São Paulo, BrazilUniv São Paulo, Dept Imunol, Lab Imunol Transplantes, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Nefrol, Dept Nefrol, Lab Imunol Clin & Expt, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, BR-04023900 São Paulo, BrazilFAPESP: 07/07139-3FAPESP: 09/52119-6FAPESP: 10/01404-0Web of Scienc

O Aluno com Paralisia Cerebral em Contexto Educativo: Diferenciação de metodologias e estratégias

O modelo de Educação Inclusiva, atualmente implementado e defendido pelas organizações internacionais, pressupõe um único sistema educacional para TODOS os alunos, partindo da aceitação das diferenças individuais e da valorização da diversidade humana, como potenciadores de capacidades num mesmo processo educacional. A Educação Inclusiva não abrange somente crianças/jovens com deficiências, mas alarga a sua intervenção a todos os que, temporária ou permanentemente, apresentem necessidades especiais. Os alunos com Necessidades Educativas Especiais de carácter motor, especialmente Paralisia Cerebral, inseridos no ensino regular, pela especificidade das manifestações apresentadas e das significativas limitações ao nível da atividade e da participação, beneficiarão com a implementação de medidas educativas que diminuam a sua situação de desvantagem e promovam o desenvolvimento das suas potencialidades, recorrendo a metodologias e estratégias facilitadoras do seu desenvolvimento global, que abordaremos numa breve revisão da literatura

Leptin Downregulates LPS-Induced Lung Injury: Role of Corticosterone and Insulin

Background/Aims: We investigated the effects of leptin in the development of lipopolysaccharide (LPS)-induced acute lung inflammation (ALI) in lean mice. Methods: Mice were administered leptin (1.0 mu g/g) or leptin (1.0 mu g/g) followed by LPS (1.5 mu g/g) intranasally. Additionally, some animals were given LPS (1.5 mu g/g) or saline intranasally alone, as a control. Tissue samples and fluids were collected six hours after instillation. Results: We demonstrated that leptin alone did not induce any injury. Local LPS exposure resulted in significant acute lung inflammation, characterized by a substantial increase in total cells, mainly neutrophils, in bronchoalveolar lavages (BAL). We also observed a significant lymphocyte influx into the lungs associated with enhanced lung expression of chemokines and cytokines (KC, RANTES, TNF-alpha, IFN-beta, GM-CSF and VEGF). LPS-induced ALI was characterized by the enhanced expression of ICAM-1 and iNOS in the lungs. Mice that received LPS showed an increase in insulin levels. Leptin, when administered prior to LPS instillation, abolished all of these effects. LPS induced an increase in corticosterone levels, and leptin potentiated this event. Conclusion: These data suggest that exogenous leptin may promote protection during sepsis, and downregulation of the insulin levels and upregulation of corticosterone may be important mechanisms in the amelioration of LPS-induced ALI.Copyright (c) 2014 S. Karger AG, BaselConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Complex Fluids INCTFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ São Paulo, Inst Biomed Sci 1, Dept Pharmacol, Lab Hypertens, BR-1524 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, BR-1524 São Paulo, BrazilUniv São Paulo, Lab Inflammat & Vasc Pharmacol, BR-05508 São Paulo, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunobiol, São Paulo, BrazilFAPESP: 12/51104-8FAPESP: 10/01404-0FAPESP: 12/02270-2FAPESP: 12/10512-6Web of Scienc

Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. in this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. in conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Instituto Nacional de Ciencia e Tecnologia de Fluidos Complexos (INCT Complex Fluids)Univ São Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, BR-05508900 São Paulo, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilUniv São Paulo, Inst Chem, Dept Biochem, BR-05508000 São Paulo, BrazilUniv São Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilFAPESP: 2009/54474-8FAPESP: 2012/02270-2FAPESP: 2013/25010-9Web of Scienc

Exercise during pregnancy protects adult mouse offspring from diet-induced obesity

Physical exercise induces positive alterations in gene expression involved in the metabolism of obesity. Maternal exercise provokes adaptations soon after birth in the offspring. Here, we investigated whether adult mouse offspring of swim-trained mothers is protected against the development of the deleterious effects of high fat diet (HFD). Our study comprises two parts. First, female C57BL/6 mice were divided into one sedentary and one swim-trained group (before and during pregnancy, n = 18). In the second part, adult offspring (n = 12) of trained and sedentary mothers was challenged to HFD for 16 weeks. Notably, most of the analysis was done in male offspring. Our results demonstrate that maternal exercise has several beneficial effects on the mouse offspring and protects them from the deleterious effects of HFD in the adult. Specifically, swimming during pregnancy leads to lower birth weight in offspring through 2 months of age. When subjected to HFD for 4 month in the adulthood, our study presents novel data on the male offspring’s metabolism of trained mothers. The offspring gained less weight, which was accompanied by less body fat, and they used more calories during daytime compared with offspring of sedentary mothers. Furthermore, we observed increased adiponectin expression in skeletal muscle, which was accompanied by decreased leptin levels and increased insulin sensitivity. Decreased interleukin-6 expression and increased peptide PYY levels were observed in sera of adult offspring of mothers that swam during pregnancy. Our results point to the conclusion that maternal exercise is beneficial to protect the offspring from developing obesity, which could be important for succeeding generations as well12FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/04757-