Butyrate Attenuates Lung Inflammation by Negatively Modulating Th9 Cells

Th9 cells orchestrate allergic lung inflammation by promoting recruitment and activation of eosinophils and mast cells, and by stimulating epithelial mucus production, which is known to be mainly dependent on IL-9. These cells share developmental pathways with induced regulatory T cells that may determine the generation of one over the other subset. In fact, the FOXP3 transcription factor has been shown to bind il9 locus and repress IL-9 production. The microbiota-derived short-chain fatty acids (SCFAs) butyrate and propionate have been described as FOXP3 inducers and are known to have anti-inflammatory properties. While SCFAs attenuate lung inflammation by inducing regulatory T cells and suppressing Th2 responses, their effects on Th9 cells have not been addressed yet. Therefore, we hypothesized that SCFAs would have a protective role in lung inflammation by negatively modulating differentiation and function of Th9 cells. Our results demonstrated that butyrate is more effective than propionate in promoting FOXP3 expression and IL-9 repression. In addition, propionate was found to negatively impact in vitro differentiation of IL-13-expressing T cells. Butyrate treatment attenuated lung inflammation and mucus production in OVA-challenged mice, which presented lower frequency of lung-infiltrated Th9 cells and eosinophils. Both Th9 cell adoptive transfer and IL-9 treatment restored lung inflammation in butyrate-treated OVA-challenged mice, indicating that the anti-inflammatory effects of butyrate may rely on suppressing Th9-mediated immune responses

Regulación de la expresión de los receptores VPAC1 y VPAC2 en linfocitos T colaboradores humanos y su implicación funcional

Debido al papel fundamental que juegan los linfocitos T CD4 en la coordinación de la respuesta inmune, la alteración y la perturbación de su actividad puede acarrear consecuencias como la aparición de procesos inflamatorios y autoinmunes. Las células T CD4 se encuentran en estrecha relación con los mediadores moleculares presentes en el microambiente, que pueden modular y alterar sus funciones y actividades. Entre esos mediadores encontramos a los neuropéptidos como VIP, el cual ha mostrado en numerosas ocasiones su potencial anti-inflamatorio u homeostático en condiciones patológicas, como la artritis reumatoide. Por ello, en la presente Tesis Doctoral, tratamos de desgranar, por un lado, la actividad del eje VIP/receptores sobre diferentes estados de activación o diferenciación de linfocitos T CD4 humanos y, por otro lado, la interacción de los receptores VPAC con los mediadores de sus rutas de señalización..

Lipopolysaccharides (LPSs)

The cytoplasm of Gram-negative bacteria is bound by three layers: an inner membrane, a layer of peptidoglycan, and an outer membrane. The outer membrane is an asymmetric lipidic bilayer, with phospholipids on its inner surface and lipopolysaccharides (LPSs) on the outside, with the latter being the major component of the outer leaflet and covering nearly three-quarters of the total outer cell surface. All LPSs possess the same general chemical architecture independently of bacterial activity (pathogenic, symbiotic, commensal), ecological niche (human, animal, soil, plant, water), or growth conditions. Endotoxins are large amphiphilic molecules consisting of a hydrophilic polysaccharide component and a covalently bound hydrophobic and highly conserved lipid component, termed lipid A (the endotoxin subunit). The polysaccharide component can be divided into two subdomains: the internal and conserved core region as well as the more external and highly variable O-specific chain, also referred to as the O-antigen due to its immunogenic properties. LPSs are endotoxins, one of the most potent class of activators of the mammalian immune system; they can be released from cell surfaces of bacteria during multiplication, lysis, and death. LPS can act through its biological center (lipid A component) on various cell types, of which macrophages and monocytes are the most important

The role of immune responses, focussing on herpes virus specificity and interferon-gamma, in Myocardial Infarction with reperfusion and in Chronic Fatigue Syndrome

Background Immune responses targeting microbes can contribute to chronic inflammation, particularly when the microbes are persistent such as herpes-family Cytomegalovirus (CMV) and EpsteinBarr virus (EBV). Such persistence of antigens can cause T cell exhaustion characterized by loss of appropriate effector functions, expression of inhibitory receptors, as well as failure to return to homeostatic pre-inflammatory conditions. This results in immune senescence and dysregulation which may cause disrupted cell populations, homing and cytokine productions that mediate immunopathology and compromise anti-microbial defences. Aims The aim of the study was to determine whether microbe specific particularly, interferongamma immune responses measured in 2 disease states, where a herpes viral inflammatory aetiology and immune dysregulation are suggested, acute Myocardial Infarction (MI) with reperfusion and Chronic Fatigue Syndrome (CFS), are indicative of disease presence and severity. Patients MI occurs due to blockage of the coronary artery, and treatment involves stent insertion, allowing reperfusion (R), which has associated immunopathology due to T cell homing. A total of 52 MI patients were studied. Blood samples were taken before and after reperfusion to investigate the dynamics of specific T cell homing to the heart, that may contribute to disease severity (reperfusion damage). For 50 CFS patients with measured disease levels, blood samples were taken to examine immune responses including those against microbes implicated in disease (CMV & EBV) compared to healthy controls. Methods T cell immunity was measured by ELIspot and flow cytometry, and cytokine levels in cell culture supernatants were measured using multiplex technology. Statistical analyses were carried out for normality in data sets. The Mann-Whitney test or unpaired t test was used to determine the difference between two unrelated groups. Differences between repeat or paired measurements were determined by Wilcoxon signed rank tests or paired t tests. Associations between measurements were investigated using Spearman correlation. Results and Discussion In MI patients, compared to before reperfusion, levels of the following cell populations fell significantly after reperfusion: terminally-differentiated CD8+ PD-1+ effector memory cells (p=0.016) and CMV-specific IFN-secreting CD4+ T cells (p=0.002) the latter also being associated with injury. This suggests specific pathogenic T cell homing to the heart during reperfusion. In CFS patients, increased disease severity was associated with increased non-specific IFNy production (p=0.008), and reduced percentage of NK cells (p=0.0047). NK cell deficiency may reduce antiviral defences and allow detrimental viral reactivation. Conclusion T cell responses against CMV appeared to have greater involvement in MI + R than CFS. Immune responses involving IFN-γ are demonstrated in both conditions as being associated with disease, and so this cytokine may be considered a disease biomarker and a therapeutic target for both