Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

CCL2 and CCR2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy

SummaryObjectiveThe role of inflammation in structural and symptomatic osteoarthritis (OA) remains unclear. One key mediator of inflammation is the chemokine CCL2, primarily responsible for attracting monocytes to sites of injury. We investigated the role of CCL2 and its receptor CCR2 in experimental OA.DesignOA was induced in 10 weeks old male wild type (WT), Ccl2−/− and Ccr2−/− mice, by destabilisation of the medial meniscus (DMM). RNA was extracted from whole joints at 6 h and 7 days post-surgery and examined by reverse transcription polymerase chain reaction (RT-PCR). Gene expression changes between naïve and DMM-operated mice were compared. Chondropathy scores, from mice at 8, 12, 16 and 20 weeks post DMM were calculated using modified Osteoarthritis Research Society International (OARSI) grading systems. Changes in hind paw weight distribution, as a measure of pain, were assessed by Linton incapacitance.ResultsAbsence of CCL2 strongly suppressed (>90%) selective inflammatory response genes in the joint 6 h post DMM, including arginase 1, prostaglandin synthase 2, nitric oxide synthase 2 and inhibin A. IL6, MMP3 and tissue inhibitor of metalloproteinase 1 were also significantly suppressed. Similar trends were also observed in the absence of CCR2. A lower average chondropathy score was observed in both Ccl2−/− and Ccr2−/− mice at 12, 16 and 20 weeks post DMM compared with WT mice, but this was only statistically significant at 20 weeks in Ccr2−/− mice. Pain-related behaviour in Ccl2−/− and Ccr2−/− mice post DMM was delayed in onset.ConclusionThe CCL2/CCR2 axis plays an important role in the development of pain in murine OA, but contributes little to cartilage damage

Alterations of CCSP expression and macrophages metabolism in the development of silica-induced pulmonary inflammation and fibrosis

Silicosis is a lethal pneumoconiosis, for which no therapy is available. Silicosis is a public health threat: more than 2.2 million people/year in the US and 230 million/year worldwide, are exposed to silica, and consequently are at increased risk of active mycobacterial tuberculosis (TB), and lung cancer. The initial response to silica is mediated by the innate immunity in a two-stage process: 1)injury of conducting epithelium at distal lung, loss of Club cells secretory protein (CCSP), and impairment of regenerative capacity; 2)phagocytosis of silica by macrophages, metabolic alterations, oxidative stress, and release of reactive-oxygen-species (ROS) and inflammatory cytokines, such as Interleukin-(IL-)1β, Tumor necrosis factor-(TNF-)α, Interferon-(IFN-)β. However, the specific role of airway epithelium and macrophage in the pathogenesis of silicosis in humans is poorly understood. This study focuses on whether silica-induced inflammation compromises the Club cells ability to regenerate bronchiolar and/or alveolar epithelium and on the macrophages metabolic alterations that occurs upon phagocytosis of silica, leading to chronic inflammation. Using wild-type and CCSP-deficient (CCSP-/-) mice we exhibit that the development of the silicotic nodules in the lung is characterized by peri-bronchiolar inflammatory cell recruitment and tissue fibrosis, that compromises the expression and proliferation of CCSP-expressing progenitor cells and limits the reparative properties of the distal airway epithelium, resulting in exacerbation of silicosis. We reveal an immunomodulatory role for CCSP in response to silica both in mice and in human lungs. Subsequently, using murine RAW 264.7 macrophage cell lines, and state- of- art techniques, such as high-resolution respirometer and liquid chromatography-high resolution mass spectrometry (LC-HRMS), to determine the effects of silica on mitochondrial respiration, and the changes in central carbon metabolism of silica-exposed macrophages, we demonstrate that in contrast to the prevalent view, crystalline silica alone induces an innate immune response without previous macrophage activation with LPS, and yet different from the one LPS-induced, since they affect differently the CII of ETC, which plays a crucial role in macrophages survival and silica-induced inflammation. Our data highlight the urgency to validate these concepts and elucidate the mechanisms underlying the silica-induced impairment of macrophages, development of inflammation and fibrosis, and consequent increased TB risk

Drosophila as a model system to study nonautonomous mechanisms affecting tumour growth and cell death

The study of cancer has represented a central focus in medical research for over a century. The great complexity and constant evolution of the pathology require the use of multiple research model systems and interdisciplinary approaches. This is necessary in order to achieve a comprehensive understanding into the mechanisms driving disease initiation and progression, to aid the development of appropriate therapies. In recent decades, the fruit fly Drosophila melanogaster and its associated powerful genetic tools have become a very attractive model system to study tumour-intrinsic and non-tumour-derived processes that mediate tumour development in vivo. In this review, we will summarize recent work on Drosophila as a model system to study cancer biology. We will focus on the interactions between tumours and their microenvironment, including extrinsic mechanisms affecting tumour growth and how tumours impact systemic host physiology

Self-renewal of macrophages: Tumor-released factors and signaling pathways

Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal

Evaluation of the effect of hypothermia by cold water immersion on blood neutrophils and lymphocytes of rats submitted to acute exercise

O estresse sistêmico induzido pelo exercício libera substâncias bioativas determinantes da mobilização neutrofílica. A crioterapia diminui a reação inflamatória e atenua a elevação da perfusão sanguínea induzida pelo exercício. O objetivo deste trabalho foi analisar a influência da hipotermia decorrente da crioimersão corporal (CIC) imediata ao esforço físico agudo nas concentrações neutrofílicas e linfocíticas no sangue. Os ratos do grupo controle (AI) foram mantidos em repouso enquanto os do grupo AII foram submetidos ao protocolo de CIC a 10ºC por 10 minutos. Enquanto os animais dos grupos BI, BII, BIII e BIV realizaram o esforço físico agudo (EFA) em água a 31ºC durante 100 minutos com sobrecarga corpórea de 5% do peso corporal, os dos grupos CI, CII, CIII e CIV foram submetidos ao EFA seguido imediatamente de CIC. Nos grupos B e C, os animais foram sacrificados nos períodos de 06 (I), 12 (II), 24 (III) e 48 (IV) horas posteriores ao EFA. Através da microscopia óptica realizou-se a contagem dos neutrófilos e linfócitos. Utilizou-se do Teste T Student para análise estatística considerando-se nível de significância p < 0,05. Observou-se uma significativa neutrofilia nos grupos AII, BI, BII, BIII, BIV, CI, CII e CIII em relação a AI, diferentemente do grupo CIV, que apresentou quantidade de neutrófilos igual ao grupo controle. Os valores de linfócitos nos grupos BII, BIII, BIV, CI e CII foram significativamente menores do que AI, e nos grupos AII, BI, CIII e CIV foram iguais a AI. A neutrofilia e a linfopenia posteriores ao intenso exercício agudo são mantidas por 48 horas ou mais, porém, mediante a aplicação da crioimersão corporal imediata ao exercício, são normalizadas em 24 horas.Systemic stress induced by exercise increases bioactive substances in plasma which leads to neutrophilic mobilization. Cryotherapy causes a decrease in the inflammatory reaction and attenuates high blood perfusion after exercise. The objective of this work was to analyze the influence of cold water immersion (CWI) after acute exercise on neutrophil and lymphocyte mobilization. A control group of rats (AI) was kept at rest and a second group (AII) was submitted to CWI at 10º C for 10 minutes. The animals of Groups BI, BII, BIII and BIV were submitted to acute exercise which consisted in swimming in water at 31º C for 100 minutes with a load equivalent to 5% of the body weight. Groups CI, CII, CIII and CIV were submitted to CWI immediately after acute exercise. The animals were sacrificed at 6 (I), 12 (II), 24 (III) and 48 (IV) hours after the exercise and neutrophil and lymphocyte cells were counted for all groups by optic microscopy. The Student t-test was used for statistical analysis with a significance level of p< 0.05. A significant increase in the number of neutrophils was observed in Groups AII, BI, BII, BIII, BIV, CI, CII and CIII compared to AI. The neutrophil count of the CIV Group was similar to the Control Group. There was a significant drop in the number of lymphocytes in Groups BII, BIII, BIV, CI and CII when compared to Group AI. The lymphocyte count of Groups AII, BI, CIII and CIV were similar to the Control Group. The changes in neutrophil and lymphocyte counts caused by acute exercise were reverted to normal at 24 hours by cold water immersion

Immunotherapy Can Enhance Anthelmintic Efficacy in Alveolar Echinococcosis

The immune response of the intermediate host with alveolar echinococcosis was investigated on mice intraperitoneally infected with Echinococcus multilocularis protoscoleces. The study was focused on cell-mediated immune response (dependent on interactions of T lymphocytes and macrophages), which is considered protective in alveolar echinococcosis. The immune response to E. multilocularis is regulated by Th1/Th2 cytokines produced by the CD4+ T lymphocyte subpopulation. Metacestode has been known for its ability to modify immune functions and suppress effective specific cell response to ensure its survival in host organism. The influence of immunomodulatory substances – muramyltripeptide (L-MTP-PE), glucan (GI), glucan with zinc (GIZn), and transfer factor (TF) – applied alone or combined with anthelmintic albendazole (ABZ) on regulative and effector components of immunity were tested and at the same time, antiparasitic efficacy of immunomodulators was evaluated

Exercise influence on immune response

ABSTRACT The study of the influence of exercise on immune response is a field in constant grow since the 1970s. The main areas studied are infection of upper respiratory airways in athletes submitted to extenuating exercises, the exercise as a model of stress and the effects of training as an adaptive mechanism to cope with stress. Exercise promotes an imbalance in organic homeostasis, and all of the systems, including the immune system, must adequate their function to this new situation. The responses to exercise can be expressed as acute response, a transitory response to stress and chronic adaptive response, when training provides better conditions for the organism to cope with stress. In both situations the components of the immune system, the cellular and humoral arms of the innate and adaptive systems, are affected by exercise. Not as a rule, one can say that moderate exercise is associated with a better function of the immune system and high intensity exercise in stressful situations is associated with a transitory state of immunodepression.RESUMO O estudo da relação entre o exercício e a resposta imune teve grande impulso a partir da metade da década de 70, tendo como principais áreas de interesse o estudo da infecção de vias aéreas superiores em atletas submetidos a grandes esforços, o exercício como modelo de estresse e a resposta do treinamento como resposta adaptativa frente a situações de estresse. A descrição da interação entre os sistemas imune e neuroendócrino foi de importância capital no desenvolvimento desses estudos. O exercício gerando um desvio da homeostase orgânica leva à reorganização das respostas de diversos sistemas, entre eles o sistema imune. É adequado dividir a resposta ao exercício em resposta aguda, resposta transitória ao estresse e resposta de adaptação crônica, na qual o treinamento capacita o organismo a lidar com o estímulo estressante de maneira mais adequada. Ambas as respostas afetam os diversos componentes do sistema imune, tanto a resposta inata em seu componente celular compreendendo neutrófilos, macrófagos e células natural killer, como em seu componente humoral, proteínas de fase aguda, sistema do complemento e enzimas, como o sistema imune adaptativo, em seu componente celular (linfócitos T e B), como no componente humoral (anticorpos e citocinas). Apesar das incorreções que cometemos quando das generalizações, podemos dizer que, de modo geral, o exercício de intensidade moderada, praticado com regularidade, melhora a capacidade de resposta do sistema imune, enquanto o exercício de alta intensidade praticado sob condições estressantes provoca um estado transitório de imunodepressão.Universidade de São Paulo Instituto de Ciencias Biologicas Departamento de HistologiaUniversidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM) Disciplina de ImunologiaUNIFESP, EPM, Disciplina de ImunologiaSciEL

Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival

The transcription factor Gata6 regulates proliferation and differentiation of epithelial and endocrine cells and cancers. Among hematopoietic cells, Gata6 is expressed selectively in resident peritoneal macrophages. We thus examined whether the loss of Gata6 in the macrophage compartment affected peritoneal macrophages, using Lyz2-Cre x Gata6flox/flox mice to tackle this issue. In Lyz2-Cre x Gata6flox/flox mice, the resident peritoneal macrophage compartment, but not macrophages in other organs, was contracted, with only a third the normal number of macrophages remaining. Heightened rates of death explained the marked decrease in peritoneal macrophage observed. The metabolism of the remaining macrophages was skewed to favor oxidative phosphorylation and alternative activation markers were spontaneously and selectively induced in Gata6-deficient macrophages. Gene expression profiling revealed perturbed metabolic regulators, including aspartoacylase (Aspa), which facilitates generation of acetyl CoA. Mutant mice lacking functional Aspa phenocopied the higher propensity to death and led to a contraction of resident peritoneal macrophages. Thus, Gata6 regulates differentiation, metabolism, and survival of resident peritoneal macrophages