Leptin-deficient ob/ob mice are overweight, develop insulin resistance, and serve as a model for type 2 diabetes (T2D). Studies suggest that inflammatory pathways are linked to the development of insulin resistance and T2D both in animals and humans. We asked whether the induction of regulatory T cells (Tregs) could alleviate the pathological and metabolic abnormalities in ob/ob mice. We induced TGF-β-dependent CD4 + latency-associated peptide (LAP)-positive Tregs by oral administration of anti-CD3 antibody plus β-glucosylceramide. We found a decrease in pancreatic islet cell hyperplasia, fat accumulation in the liver, and inflammation in adipose tissue, accompanied by lower blood glucose and liver enzymes. In addition, treated animals had decreased CD11b + F4/80 + macrophages and TNF-α in adipose tissue. Adoptive transfer of orally induced CD4 + LAP + Tregs ameliorated metabolic and cytokine abnormalities. Our results demonstrate the importance of inflammation in T2D and identify a unique immunological approach for treatment of T2D by the induction of Tregs.eptin-deficient ob/ob mice are overweight, develop severe insulin resistance elevated liver enzymes, and serve as a model for type 2 diabetes (T2D) and the metabolic syndrome (1, 2). These mice are characterized by an absence of functional leptin, thymic atrophy, and defective immune responses manifested by reduced antigen-specific T-cell proliferation and abnormalities in the number and function of dendritic cells (DCs), regulatory T cells (Tregs), and natural killer T (NKT) cells (3, 4). In recent years, it has become clear that inflammation plays an important role in insulin resistance, and the pathogenesis of T2D with experiments showed that adipose tissue-derived proinflammatory cytokines such as TNF-α could cause insulin resistance in experimental models (5-7). Subsequently, other fat-derived cytokines and bioactive substances such as IL-6, IL-1β, and monocyte chemoattractant protein-1 have been identified (8), and investigators have found that obese adipose tissue is characterized by macrophage infiltration, which serves as an important source of inflammation (9-11).These observations raise the possibility that therapeutical strategies designed to decrease inflammation in adipose tissue might have a beneficial effect in T2D. Indeed, early experiments suggested that the antiinflammatory effects of salicylates have an ameliorating effect in T2D (12, 13), and recent studies report that IL-1 receptor antagonists may be beneficial in T2D (14).Tregs play an important role in the maintenance of immunological self-tolerance and have been shown in experimental models to inhibit the development of autoimmune diseases by suppressing potentially autoreactive T cells (15). Treg function is being investigated in a wide range of human inflammatory and infectious diseases and cancer (16-18). We hypothesized that the induction of Tregs might have an ameliorating effect in the ob/ob model of T2D. Consistent with this hypothesis, in a recent report, investigators found ...
Hypertension is a major global health challenge, as it represents the main risk factor for stroke and cardiovascular disease. It is a multifactorial clinical condition characterized by high and sustained levels of blood pressure, likely resulting from a complex interplay of endogenous and environmental factors. The gut microbiota has been strongly supposed to be involved but its role in hypertension is still poorly understood. In an attempt to fill this gap, here we characterized the microbial composition of fecal samples from 48 hypertensive and 32 normotensive Brazilian individuals by nextgeneration sequencing of the 16S rRNA gene. In addition, the cytokine production of peripheral blood samples was investigated to build an immunological profile of these individuals. We identified a dysbiosis of the intestinal microbiota in hypertensive subjects, featured by reduced biodiversity and distinct bacterial signatures compared with the normotensive counterpart. Along with a reduction in Bacteroidetes members, hypertensive individuals were indeed mainly characterized by increased proportions of Lactobacillus and Akkermansia while decreased relative abundances of well-known butyrate-producing commensals, including Roseburia and Faecalibacterium within the Lachnospiraceae and Ruminococcaceae families. We also observed an inflamed immune profile in hypertensive individuals with an increase in TNF/IFN-γ ratio, and in TNF and IL-6 production when compared to normotensive ones. Our work provides the first evidence of association of hypertension with altered gut microbiota and inflammation in a Brazilian population. While lending support to the existence of potential microbial signatures of hypertension, likely to be robust to age and geography, our findings point to largely neglected bacteria as potential contributors to intestinal homeostasis loss and emphasize the high vulnerability of hypertensive individuals to inflammation-related disorders.
Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase severity of autoimmune diseases. The purpose of the present study was to evaluate the effects of a diet supplemented with NaCl in the colonic mucosa at steady state and during inflammation. We showed that consumption of HSD by mice triggered a gut inflammatory reaction associated with IL-23 production, recruitment of neutrophils, and increased frequency of the IL-17-producing type 3 innate lymphoid cells (ILC3) in the colon. Moreover, gut inflammation was not observed in IL-17-/-mice but it was present, although at lower grade, in RAG −/− mice suggesting that the inflammatory effects of HSD was dependent on IL-17 but only partially on Th17 cells. Expression of SGK1, a kinase involved in sodium homeostasis, increased 90 min after ingestion of 50% NaCl solution and decreased 3 weeks after HSD consumption. Colitis induced by oral administration of either dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid was exacerbated by HSD consumption and this effect was associated with increased frequencies of RORγt + CD4 + T cells and neutrophils in the colon. Therefore, our results demonstrated that consumption of HSD per se triggered a histologically detectable inflammation in the colon and also exacerbated chemically induced models of colitis in mice by a mechanism dependent on IL-17 production most likely by both ILC3 and Th17 cells.
In the present study, C57BL/6 mice were inoculated with metacyclic Leishmania amazonensis or L. braziliensis promastigotes. While these animals were capable of controlling the infection by L. braziliensis, they developed chronic lesions with elevated numbers of parasites when infected by L. amazonensis. The differences in parasite control were associated with a decreased production of IFN-gamma and TNF by lymph node cells from L. amazonensis-infected mice. Furthermore, these animals presented decreased spleen cell proliferation and activation of germinal centers. In addition, we compared the ability of these parasites to hydrolyze extracellular ATP and AMP. While the ATPase activity of both parasite species was similar, L. amazonensis promastigotes presented higher AMP hydrolytic activity. This increased activity may lead to an increased production of adenosine, which has been shown to present anti-inflammatory activity and may thus be involved in the establishment of the immunosuppression observed in mice infected by L. amazonensis.
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