Acetylsalicylic acid modulates inflammation and insulin resistance in a mouse model of diet-induced obesity

Extensive scientific evidence indicates that non-optimal diet and sedentary lifestyle constitute some of the behaviors/risk factors associated with the onset of many diseases with significant societal impact, such as obesity. Chronic over-nutrition dramatically remodels adipose tissue architecture, driving adipocyte hypertrophy, oxidative stress and immune cell infiltration, followed by increased production of proinflammatory adipokines and cytokines that contribute to the progression of a chronic, low-grade inflammatory state (1,2). Obesity is associated with this inflammatory phenotype and increases the risk of chronic disease, including cardiovascular disease, as well as insulin resistance that predisposes to the development of type 2 diabetes (3). These obesity-associated diseases are subsequently linked to premature death, and reinforce the need to further define the complex relationship between inflammation and adipose tissue dysfunction. Reducing inflammation may represent a feasible disease-prevention strategy for obesity. Here we evaluate the effects of acetylsalicylic acid (ASA), a commercial small-molecule anti-inflammatory drug, in a mouse model of diet-induced obesity (DIO). The metabolic and inflammatory status and adipose tissue changes were evaluated by immunohistochemistry and Real time PCR in mice fed with high fat diet (HFD) compared with mice fed with standard diet (SD). We also analyzed how these events were modified as a result of treatment with ASA. Our results demonstrate that ASA not only displays anti-adiposity effects by reducing adipocyte hypertrophy and reversing insulin resistance, but that it also modulates adipose tissue inflammation. This could aid the optimization of clinical interventions and lifestyle changes aimed at improving human health

Periodic Accumulation of Regulatory T Cells in the Uterus: Preparation for the Implantation of a Semi-Allogeneic Fetus?

BACKGROUND: Naturally occurring Foxp3(+)regulatory T cells play an important role in the inhibition of an immunological attack of the fetus. As implantation of the fetus poses an immediate antigenic challenge, the immune system has to prepare itself for this event prior to implantation. METHODOLOGY AND PRINCIPAL FINDINGS: Here, we show using quantitative RT-PCR and flow cytometry that regulatory T cells accumulate in the uterus not only during pregnancy, but also every time the female becomes fertile. Their periodic accumulation is accompanied by matching fluctuations in uterine expression of several chemokines, which have been shown to play a role in the recruitment and retention of regulatory T cells. CONCLUSIONS/SIGNIFICANCE: The data lead us to propose that every time a female approaches estrus, regulatory T cells start to accumulate in the uterus in preparation for a possible implantation event. Once pregnancy is established, those regulatory T cells that have seen alloantigen need to be retained at their site of action. Whilst several chemokines appear to be involved in the recruitment and/or retention of regulatory T cells during estrus, in pregnancy this role appears to be taken over by CCL4

CXCL12 Mediates Aberrant Costimulation of B Lymphocytes in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Immunodeficiency

The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity

Variation of chemokine expression in the uterus during the mouse estrus cycle and pregnancy.

<p>Relative levels of (a) CCL3, (b) CCL4, (c) CCL22 and (d) CX3CL1 were determined by quantitative RT-PCR performed on total uterine mRNA, normalised to HPRT on the same sample set used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000382#pone-0000382-g001" target="_blank">Fig. 1</a>. Levels for the 4 estrus cycle phases are shown in chronological order and compared to the levels in pregnant mice. Each point corresponds to one animal. Horizontal bars represent the mean of each data set. Dotted lines indicate the maximal and minimal values detected for pregnant mice.</p

Foxp3 and chemokine expression level fluctuations during the estrus cycle and pregnancy.

<p>Plots of the variation of the mean relative expression of Foxp3, CCL3, CCL4, CCL5, CCL22 and CX3CL1 during the estrus cycle phases and pregnancy (same sample set used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000382#pone-0000382-g001" target="_blank">Figs. 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000382#pone-0000382-g002" target="_blank">2</a>). Estrus cycle phases are arranged in chronological order: (d) diestrus>(p) pro-estrus>(e) estrus>(m) met-estrus>(d) diestrus etc. After 2 full cycles, a cycle were estrus is followed by (P) pregnancy is shown. Dots represent the mean of each data set. Sinusoidal functions (black lines) were fitted to the estrus cycle data (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000382#s4" target="_blank">methods</a>). In the cases where the sinusoidal function did not fit the data, a line connecting the means is shown (red line). Dotted lines join the mean of the estrus phase of the last cycle with the mean of the levels detected during pregnancy.</p

Regulatory T cells protect from autoimmune arthritis during pregnancy

Pregnancy frequently has a beneficial effect on the autoimmune disease Rheumatoid Arthritis, ranging from improvement in clinical symptoms to complete remission. Despite decades of study, a mechanistic explanation remains elusive. Here, we demonstrate that an analogous pregnancy-induced remission can be observed in a mouse model of arthritis. We demonstrate that during pregnancy mice are protected from collagen-induced arthritis, but are still capable of launching normal immune responses to influenza infections. We examine the role of regulatory T (TR) cells in this beneficial effect. TR cells are essential for many aspects of immune tolerance, including the suppression of autoimmune responses. Remarkably, transfer of regulatory T cells from pregnant ‘protected’ mice was sufficient to confer protection to non-pregnant mice. These results suggest that regulatory T cells are responsible for the pregnancy-induced amelioration of arthritis

Alloantigen-enhanced accumulation of CCR5(+) ‘effector’ regulatory T cells in the gravid uterus

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive CCR5(+) and a far less suppressive CCR5(−) subpopulation, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T cells from CCR5(−/−) gene deletion mutants still suppress, they are less effective mediators of maternal–fetal tolerance. The accumulation of CCR5(+) regulatory T cells at this site appears to be enhanced by alloantigen. This finding is in stark contrast to the systemic expansion of regulatory T cells during pregnancy, which appears to be alloantigen-independent. The fact that CCR5(+) regulatory T cells preferentially accumulate in the gravid uterus and that expression of CCR5 on regulatory T cells can be induced by activation lead us to propose that CCR5 is responsible for the accumulation of those regulatory T cells that have been activated by paternal antigens

CXCL12 mediates aberrant costimulation of B lymphocytes in warts, hypogammaglobulinemia, infections, myelokathexis immunodeficiency

The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation. Searching for a mechanistic explanation for these observations, we uncovered a novel costimulatory effect of CXCL12, the CXCR4 ligand, on WHIM-mutant but not wild-type B cells. The WHIM CXCR4-mediated costimulation led to increased B-cell activation, possibly involving mTOR, albeit without concurrently promoting survival. A reduction in antigenic load during immunization in the mouse was able to circumvent the adaptive immunity defects. These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity