Differentiation of circulating monocytes into macrophages with metabolically activated phenotype regulates inflammation in dyslipidemia patients.

Macrophages are mediators of inflammation having an important role in the pathogenesis of cardiovascular diseases. Recently, a pro-inflammatory subpopulation, known as metabolically activated macrophages (MMe), has been described in conditions of obesity and metabolic syndrome where they are known to release cytokines that can promote insulin resistance. Dyslipidemia represents an important feature in metabolic syndrome and corresponds to one of the main modifiable risk factors for the development of cardiovascular diseases. Circulating monocytes can differentiate into macrophages under certain conditions. They correspond to a heterogeneous population, which include inflammatory and anti-inflammatory subsets; however, there is a wide spectrum of phenotypes. Therefore, we decided to investigate whether the metabolic activated monocyte (MoMe) subpopulation is already present under dyslipidemia conditions. Secondly, we assessed whether different levels of cholesterol and triglycerides play a role in the polarization towards the metabolic phenotype (MMe) of macrophages. Our results indicate that MoMe cells are found in both healthy and dyslipidemia patients, with cells displaying the following metabolic phenotype: CD14varCD36+ABCA1+PLIN2+. Furthermore, the percentages of CD14++CD68+CD80+ pro-inflammatory monocytes are higher in dyslipidemia than in healthy subjects. When analysing macrophage differentiation, we observed that MMe percentages were higher in the dyslipidemia group than in healthy subjects. These MMe have the ability to produce high levels of IL-6 and the anti-inflammatory cytokine IL-10. Furthermore, ABCA1 expression in MMe correlates with LDL serum levels. Our study highlights the dynamic contributions of metabolically activated macrophages in dyslipidemia, which may have a complex participation in low-grade inflammation due to their pro- and anti-inflammatory function.

Marine peptides as immunomodulators: Californiconus californicus-derived synthetic conotoxins induce IL-10 production by regulatory T cells (CD4+Foxp3+).

Context: CD4+ T lymphocytes are able to differentiate into distinct subtypes according to several immunological scenarios, including T helper (Th)1, Th2, Th17 and regulatory T (Treg) cells. CD4+ T cells are phenotypically flexible and have specific ion channels, such as the nicotinic acetylcholine receptors (nAChR) that could be modulated by peptides produced by marine snails, known as conotoxins. Their effect on T lymphocytes has not been explored and emerging evidence suggests that these peptides may have immunomodulatory activities. Objective: This study investigated the effect of two Californiconus californicus-derived synthetic conotoxins on the proliferation and differentiation of T lymphocyte subpopulations Th1, Th2, Th17 and Treg. Methods: Cells from lymph nodes of BALB/c mice were cultured in the presence of conotoxins cal14.1b and cal14.2c (5.5 µM), during 96 h. Cell proliferation and intracellular cytokine production (IFN-γ, IL-4, IL-17 and IL-10) were analyzed by flow cytometry. Results and Discussion: cal14.1b and cal14.2c increased intracellular IL-10 production in Treg (CD3+CD4+Foxp3+) cells and decreased intracellular IL-17 production (CD3+CD4+) after 72 h of culture. Conotoxins did not show any effect on T cell proliferation nor Th1/Th2 balance. Conclusion: These results suggest that synthetic conotoxins exert immunomodulatory activity, especially by regulating specific functions on T lymphocytes.

Interleukin-10 responses from acute exercise in healthy subjects: A systematic review.

PURPOSE: Interleukin 10 (IL-10) is a cytokine that plays a critical role with potent anti-inflammatory properties when produced during exercise, limiting host immune response to pathogens and preventing tissue damage. The purpose of this systematic review was to assess the response of IL-10 after acute exercise session in healthy adults. METHODS: Databases of Ovid Medline (1978-2016), CINAHL (1998-2016), EMBASE (2003-2016), SportDiscus (1990-2016), and Web of Science library (1990-2016) were carefully screened. Clinical trials comparing exercise types in healthy individuals were included for pooled analysis. The trials of exercise were methodologically appraised by PEDro Scale. RESULTS: Twelve randomized controlled and crossover trials containing 176 individuals were identified for inclusion. The Kruskal-Wallis test showed no significant differences between type of exercise and the corresponding values in IL-10 [X2(4) = 2.878; p = 0.449]. The duration of exercise was significantly correlated with increase in IL-10 changes (Pearson's r = 1.00, 95%CI: 0.015-0.042, p < 0.0001) indicating that 48% of the variation in IL-10 levels can be explained by the duration of the exercise performed. In addition, despite a linear increase, we did not find a significant correlation with the intensity of exercise and IL-10 changes (Pearson's r = 0.218, 95%CI: -0.554-0.042, p < 0.035). CONCLUSION: Overall, the duration of the exercise is the single most important factor determining the magnitude of the exercise-induced increase of plasma IL-10.

Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway.

Electrical stimulation of the vagus nerve (VNS) is a novel strategy used to treat inflammatory conditions. Therapeutic VNS activates both efferent and afferent fibers; however, the effects attributable to vagal afferent stimulation are unclear. Here, we tested if selective activation of afferent fibers in the abdominal vagus suppresses systemic inflammation. In urethane-anesthetized rats challenged with lipopolysaccharide (LPS, 60 µg/kg, i.v.), abdominal afferent VNS (2 Hz for 20 min) reduced plasma tumor necrosis factor alpha (TNF) levels 90 min later by 88% compared with unmanipulated animals. Pre-cutting the cervical vagi blocked this anti-inflammatory action. Interestingly, the surgical procedure to expose and prepare the abdominal vagus for afferent stimulation ('vagal manipulation') also had an anti-inflammatory action. Levels of the anti-inflammatory cytokine IL-10 were inversely related to those of TNF. Prior bilateral section of the splanchnic sympathetic nerves reversed the anti-inflammatory actions of afferent VNS and vagal manipulation. Sympathetic efferent activity in the splanchnic nerve was shown to respond reflexly to abdominal vagal afferent stimulation. These data demonstrate that experimentally activating abdominal vagal afferent fibers suppresses systemic inflammation, and that the efferent neural pathway for this action is in the splanchnic sympathetic nerves.