Circulating JKAP levels may correlate with postpartum anxiety and depression through its interaction with T helper 17 cells.

Jun N-terminal kinase pathway-associated phosphatase (JKAP) regulates CD4+ T-cell differentiation and immunity, which are linked to mental disorders. This study aimed to explore the relationships between JKAP and T helper 17 (Th17)/regulatory T (Treg) ratio, as well as their associations with anxiety and depression in postpartum women. Serum JKAP were measured by enzyme-linked immunosorbent assay and blood Th17 and Treg cells were measured by flow cytometry in 250 postpartum women. Anxiety and depression were evaluated by the 6-item State-Trait Anxiety Inventory (STAI6) and Edinburgh Postnatal Depression Scale (EPDS). Anxiety and depression rates were 22.0 and 28.4%, respectively, among postpartum women. Notably, JKAP was negatively associated with the STAI6 (P=0.002) and EPDS scores (P<0.001) in postpartum women and was lower in postpartum women with anxiety (P=0.023) or depression (P=0.002) than in those without. Moreover, JKAP was inversely related to Th17 cells and Th17/Treg ratio but positively correlated with Treg cells in postpartum women (all P<0.001). Interestingly, Th17 cells and Th17/Treg ratio were both positively associated with STAI6 and EPDS scores in postpartum women (all P<0.001). Furthermore, Th17 cells and Th17/Treg ratio were lower in postpartum women with anxiety or depression than in those without (all P<0.01). Nevertheless, Treg cells were not linked to anxiety or depression in postpartum women. JKAP was negatively associated with Th17 cells and Th17/Treg ratio; moreover, they all related to anxiety and depression in postpartum women, indicating that JKAP may be involved in postpartum anxiety and depression via interactions with Th17 cells.

Phenotypes of regulatory T cells in different stages of COPD.

BACKGROUND: Previous studies have shown that failure to control inflammatory processes mediated by regulatory T (Treg) cells contributes to chronic obstructive pulmonary disease (COPD) development and progression. The activity of Treg cells depends on their phenotypic characteristics: resting Treg (rTreg, CD3+CD4+CD25+FOXP3+CD25++CD45RA+) and activated Treg (aTreg, CD3+CD4+CD25+FOXP3+CD25+++CD45RA-) cells exhibit immunosuppressive activity, while cytokine-secreting T cells (FrIII, CD3+CD4+CD25+FOXP3+CD25++CD45RA-) exhibit proinflammatory activity. Previous findings have shown an increased density of cytokine-secreting T cells in COPD patients experiencing exacerbation. However, the methods for evaluating COPD under stable conditions are lacking. AIM: To evaluate Treg cell phenotypes in patients with different stages of COPD under stable conditions. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from non-obstructed smokers and ex-smokers (NOS group, n = 19) and COPD patients at different stages (COPD I-II group, n = 25; COPD III-IV group, n = 25). The phenotypic characteristics of Treg cells and Th17 cells and their respective intracellular cytokines were analyzed by flow cytometry. RESULTS: Both obstructed groups showed an increase in the proportion of rTregs, while the COPD III-IV group showed additional increases in total Treg and Th17 cells and in IL-10+ cells. There was an increase in proinflammatory mediators (CD3+CD4+IL-17+ cells; CD3+CD4+RORγt+ cells) in the COPD I-II group. In contrast, the NOS group demonstrated high proportions of proinflammatory Treg cells and proinflammatory CD8+ T cells (CD3+CD8+IL-17+). CONCLUSION: Despite the increase in both total Treg cells and the rTreg phenotype from the early stages of COPD, there was a decrease in cells expressing IL-10, suggesting a failure in controlling the inflammatory process. These events precede the progression of the inflammatory process mediated by Th17 cells.

Effector CD4+ T-cell subsets in Takayasu arteritis-differences between the peripheral blood and the aorta.

Takayasu arteritis (TAK) is a granulomatous vasculitis that affects large arteries. T cells are important in TAK pathophysiology as these cells orchestrate granulomatous infiltration in arteries. This study aims to evaluate effector CD4+ T cells in the peripheral blood and the aortic wall of TAK patients and to analyze associations with disease activity and therapy. We performed a longitudinal study including 30 TAK patients and 30 controls. CD3+ T cells, CD3+CD4- T cells, CD4+ T cells, and Th1, Th2, and Th17 cells were evaluated in peripheral blood by flow cytometry, and the expression of CD4, CD8, Tbet, GATA-3, and RORγT was analyzed in the aorta of six patients by immunohistochemistry. TAK patients presented lower CD3+ T cells and CD4+ T cells (P = 0.031 and P = 0.039, respectively) than controls. Patients with active disease and those in remission had higher proportions of Th17 cells than controls (P = 0.016 and P = 0.004, respectively). Therapy for TAK did not result in significant differences concerning CD4+ effector T-cell subpopulations. Disease duration correlated with the number and percentage of Th2 cells (rho = -0.610 and rho = -0.463, respectively) and with Th17 cells (rho = -0.365 and rho = -0.568). In the aorta, the expression of CD8 was higher than CD4, whereas GATA-3, Tbet, and RORγT were expressed in this order of frequency. In conclusion, TAK patients present an increased Th17 response in the peripheral blood regardless of disease activity, whereas in the aortic tissue CD8 cells and the Th2 response were predominant.

Differential Response of Human Dendritic Cells upon Stimulation with Encapsulated or Non-Encapsulated Isogenic Strains of Porphyromonas gingivalis.

During periodontitis, the extracellular capsule of Porphyromonas gingivalis favors alveolar bone loss by inducing Th1 and Th17 patterns of lymphocyte response in the infected periodontium. Dendritic cells recognize bacterial antigens and present them to T lymphocytes, defining their activation and polarization. Thus, dendritic cells could be involved in the Th1 and Th17 response induced against the P. gingivalis capsule. Herein, monocyte-derived dendritic cells were obtained from healthy individuals and then stimulated with different encapsulated strains of P. gingivalis or two non-encapsulated isogenic mutants. Dendritic cell differentiation and maturation were analyzed by flow cytometry. The mRNA expression levels for distinct Th1-, Th17-, or T-regulatory-related cytokines and transcription factors, as well as TLR2 and TLR4, were assessed by qPCR. In addition, the production of IL-1ß, IL-6, IL-23, and TNF-α was analyzed by ELISA. The encapsulated strains and non-encapsulated mutants of P. gingivalis induced dendritic cell maturation to a similar extent; however, the pattern of dendritic cell response was different. In particular, the encapsulated strains of P. gingivalis induced higher expression of IRF4 and NOTCH2 and production of IL-1ß, IL-6, IL-23, and TNF-α compared with the non-encapsulated mutants, and thus, they showed an increased capacity to trigger Th1 and Th17-type responses in human dendritic cells.

Chronic psychological stress aggravates psoriasis-like skin inflammation via overactivation of ß2-adrenoceptor and nuclear factor kappa B pathways.

The relationship between psoriasis severity and psychological stress has been described in several studies. However, the mechanism by which chronic stress exacerbates psoriasis is not completely understood. This study aimed at investigating whether chronic psychological stress can aggravate psoriasis-like skin inflammation. Mice were subjected to a restraint stress model and topically treated with imiquimod (IMQ). Differentiated human keratinocytes were treated with high epinephrine levels and IMQ in vitro. Stress aggravated macroscopic features and the increase in epidermal thickness induced by IMQ in mouse skin. The increase in NF-κB and IL-17A expression induced by IMQ was potentiated by chronic stress in mouse skin. The skin of stressed mice treated with IMQ showed higher levels of ß2-adrenergic receptors (ß2-AR). In human keratinocytes, high epinephrine levels exacerbated the increase in the levels of ß2-AR and IL-17A induced by IMQ. ß-AR antagonist reversed the effects of chronic stress in IMQ-induced inflammation both in vivo and in vitro. In conclusion, stress-stimulated overactivation of the ß2-AR and NF-κB pathways potentiates a Th1/Th17 profile leading to an exacerbation of psoriasis.

Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection.

In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1ß and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

Effect of crosstalk between Th17 and Th9 cells on the activation of dermal vascular smooth muscle cells in systemic scleroderma and regulation of tanshinone IIA.

BACKGROUND: To evaluate the effect of T-helper 17 (Th17) cells and Th9 cells on the activation of dermal vascular smooth muscle cells (DVSMCs) in systemic scleroderma (SSc) and regulation of tanshinone IIA. METHODS: The expression of interleukin 17 receptor (IL-17R) and interleukin 9 receptor (IL-9R) in the skin of SSc patients was assessed by immunofluorescence. The expression of IL-9 and IL-9R mRNA in peripheral blood mononuclear cells (PBMCs) of SSc patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The proportion of Th9 cells in PBMCs of SSc patients was sorted by flow cytometry. The effect of IL-9 on the differentiation of Th17 and IL-17 on that of Th9 was detected by flow cytometry. The proportion of Th9 and Th17 cells in SSc patients was detected by flow cytometry. The level of collagen I, III, α-SMA, IL-9R, IL-17R, JNK, P38, and ERK were analyzed using western blot (WB). RESULTS: Th9 cells were highly expressed in SSc. IL-9 stimulated the differentiation of immature T cells into Th17 cells. IL-17 induced the differentiation of immature T cells into Th9 cells. Tanshinone IIA inhibited the differentiation of immature T lymphocytes into Th17 and Th9. WB showed that the combined action of IL-17 and IL-9 upregulated the inflammation and proliferation of DVSMCs. Anti-IL17, anti-IL9, and tanshinone IIA inhibited the functional activation of DVSMCs. STUDY LIMITATIONS: For Th17, Th9 and vascular smooth muscle cells, the study on the signal pathway of their interaction is not thorough enough. More detailed studies are needed to explore the mechanism of cell-cell interaction. CONCLUSIONS: The current results suggested that Th17 and Th9 cells induced the activation of DVSMCs in SSc through crosstalk in vitro, and tanshinone IIA inhibited the process.

Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39+Treg cell subsets in response to myelin antigen in multiple sclerosis patients.

BACKGROUND: Mood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells. OBJECTIVES: We aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients. METHODS: For our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated. RESULTS: Here, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen. CONCLUSIONS: In summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity.

Involvement of Th1Th17 Cell Subpopulations in the Immune Responses of Mothers Who Gave Birth to Children with Congenital Zika Syndrome (CZS).

High levels of T helper 17 cell (Th17)-related cytokines have been shown in acute Zika virus (ZIKV) infection. We hypothesized that the high levels of Th17-related cytokines, associated with a regulatory environment during pregnancy, create a favorable milieu for the differentiation of CD4+Th17 cells. We present data from a cross-sectional study on mothers who confirmed ZIKV infection by qRT-PCR and their children. We also recruited non-pregnant women infected with ZIKV in the same period. ZIKV infection occurred between 2015 and 2017. We collected samples for this study between 2018 and 2019, years after the initial infection. We highlight that, after in vitro stimulation with ZIKV CD4 megapool (ZIKV MP), we found a lower frequency of IL-17-producing CD4+ T cells (Th17), especially in the mothers, confirmed by the decrease in IL-17 production in the supernatant. However, a higher frequency of CD4+ IL-17+ IFN-γ+ T cells (Th1Th17) responding to the ZIKV MP was observed in the cells of the mothers and children but not in those of the non-pregnant women. Our data indicate that the priming of CD4 T cells of the Th1Th17 phenotype occurred preferentially in the mothers who gave birth to children with CZS and in the children.

SOCS2 expression in hematopoietic and non-hematopoietic cells during Trypanosoma cruzi infection: Correlation with immune response and cardiac dysfunction.

Chagas disease has a complex pathogenesis wherein the host immune response is essential for controlling its development. Suppressor of cytokine signaling(SOCS)2 is a crucial protein that regulates cytokine production. In this study, SOCS2 deficiency resulted in an initial imbalance of IL12- and IL-10-producing neutrophils and dendritic cells (DCs), which caused a long-lasting impact reducing inflammatory neutrophils and DCs, and tolerogenic DCs at the peak of acute disease. A reduced number of inflammatory and pro-resolving macrophages, and IL17A-producing CD4+ T cells, and increased lymphocyte apoptosis was found in SOCS2-deficient mice. Electrocardiogram analysis of chimeric mice showed that WT mice that received SOCS2 KO bone marrow transplantation presented increased heart dysfunction. Taken together, the results demonstrated that SOCS2 is a crucial regulator of the immune response during Trypanosoma cruzi infection, and suggest that a SOCS2 genetic polymorphism, or failure of its expression, may increase the susceptibility of cardiomyopathy development in Chagasic patients.

Th17/Treg Imbalance in Chronic Obstructive Pulmonary Disease: Clinical and Experimental Evidence.

The imbalance between pro- and anti-inflammatory immune responses mediated by Th17 and Treg cells is deeply involved in the development and progression of inflammation in chronic obstructive pulmonary disease (COPD). Several clinical and experimental studies have described the Th17/Treg imbalance in COPD progression. Due to its importance, many studies have also evaluated the effect of different treatments targeting Th17/Treg cells. However, discrepant results have been observed among different lung compartments, different COPD stages or local and systemic markers. Thus, the data must be carefully examined. In this context, this review explores and summarizes the recent outcomes of Th17/Treg imbalance in COPD development and progression in clinical, experimental and in vitro studies.

A specific structure and high richness characterize intestinal microbiota of HIV-exposed seronegative individuals.

Intestinal microbiota facilitates food breakdown for energy metabolism and influences the immune response, maintaining mucosal homeostasis. Overall, HIV infection is associated with intestinal dysbiosis and immune activation, which has been related to seroconversion in HIV-exposed individuals. However, it is unclear whether microbiota dysbiosis is the cause or the effect of immune alterations and disease progression or if it could modulate the risk of acquiring the HIV infection. We characterize the intestinal microbiota and determine its association with immune regulation in HIV-exposed seronegative individuals (HESN), HIV-infected progressors (HIV+), and healthy control (HC) subjects. For this, feces and blood were collected. The microbiota composition of HESN showed a significantly higher alpha (p = 0.040) and beta diversity (p = 0.006) compared to HC, but no differences were found compared to HIV+. A lower Treg percentage was observed in HESN (1.77%) than HC (2.98%) and HIV+ (4.02%), with enrichment of the genus Butyrivibrio (p = 0.029) being characteristic of this profile. Moreover, we found that Megasphaera (p = 0.017) and Victivallis (p = 0.0029) also are enriched in the microbiota composition in HESN compared to HC and HIV+ subjects. Interestingly, an increase in Succinivibrio and Prevotella, and a reduction in Bacteroides genus, which is typical of HIV-infected individuals, were observed in both HESN and HIV+, compared to HC. Thus, HESNs have a microbiota profile, similar to that observed in HIV+, most likely because HESN are cohabiting with their HIV+ partners.

Effects of Molecular Iodine/Chemotherapy in the Immune Component of Breast Cancer Tumoral Microenvironment.

Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the immune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in the expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFß; p = 0.049), whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFß in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

Interleukin-1 Links Autoimmune and Autoinflammatory Pathophysiology in Mixed-Pattern Psoriasis.

Autoinflammatory and autoimmune diseases are characterized by an oversensitive immune system with loss of the physiological endogenous regulation, involving multifactorial self-reactive pathological mechanisms of mono- or polygenic nature. Failure in regulatory mechanisms triggers a complex network of dynamic relationships between innate and adaptive immunity, leading to coexistent autoinflammatory and autoimmune processes. Sustained exposure to a trigger or a genetic alteration at the level of the receptors of the natural immune system may lead to abnormal activation of the innate immune system, adaptive system activation, loss of self-tolerance, and systemic inflammation. The IL-1 family members critically activate and regulate innate and adaptive immune responses' diversity and plasticity in autoimmune and/or autoinflammatory conditions. The IL-23/IL-17 axis is key in the communication between innate immunity (IL-23-producing myeloid cells) and adaptive immunity (Th17- and IL-17-expressing CD8+ T cells). In psoriasis, these cytokines are decisive to the different clinical presentations, whether as plaque psoriasis (psoriasis vulgaris), generalized pustular psoriasis (pustular psoriasis), or mixed forms. These forms reflect a gradient between autoimmune pathophysiology with predominant adaptive immune response and autoinflammatory pathophysiology with predominant innate immune response.

Simulation Model for Hashimoto Autoimmune Thyroiditis Disease.

Hashimoto thyroiditis (HT) is a pathology that often causes a gradual thyroid insufficiency in affected patients due to the autoimmune destruction of this gland. The cellular immune response mediated by T helper lymphocytes TH1 and TH17 can induce the HT disease. In this pathologic condition, there is an imbalance between the TH17 and Treg lymphocytes as well as a gut microbiota dysfunction. The objective of this work was to describe the interactions of the cell subpopulations that participate in HT. To achieve this goal, we generated a mathematical model that allowed the simulation of different scenarios for the dynamic interaction between thyroid cells, the immune system, and the gut microbiota. We used a hypothetical-deductive design of mathematical modeling based on a system of ordinary differential equations, where the state variables are the TH1, TH17, and Treg lymphocytes, the thyrocytes, and the bacteria from gut microbiota. This work generated a compartmental model of the cellular immune response occurring in the thyroid gland. It was observed that TH1 and TH17 lymphocytes could increase the immune cells' activity, as well as activate effector cells directly and trigger the apoptosis and inflammation processes of healthy thyrocytes indirectly. Likewise, the model showed that a reduction in Treg lymphocytes could increase the activity of TH17 lymphocytes when an imbalance of the gut microbiota composition occurred. The numerical results highlight the TH1, TH17, and bacterial balance of the gut microbiota activities as important factors for the development of HT disease.

Major Depressive Disorder Enhances Th2 and Th17 Cytokines in Patients Suffering from Allergic Rhinitis and Asthma.

INTRODUCTION: Major depressive disorder (MDD) can impact the severity of allergic rhinitis (AR) and asthma (AA). Here, we evaluated the cytokine production by T-cells from AR and AA patients with or without MDD. The effect of serotonin on the in vitro T-cell response was also evaluated. METHODS: The cytokines produced by activated T-cells were measured by Luminex and flow cytometry. In some cell cultures, serotonin was added. RESULTS: MDD not only enhanced the production of Th2- and Th17-related cytokines, but also, the levels of interleukin (IL)-5 and IL-17 were directly correlated with the severity of depression and anxiety symptoms. As compared with AR, the levels of IL-17 were higher and the release of IL-10 was lower in activated T-cell cultures from AA patients, mainly those with MDD. In AA/MDD patients, the severity of anxiety symptoms and lung disease was directly correlated with Th17-like and hybrid Th2/Th17 cells, but inversely correlated with IL-10-secreting CD4+ T-cells. Finally, the addition of serotonin reduced the production of Th2- and Th17-related cytokines, but elevated IL-10 secretion in cell cultures from both AR and AA patients. CONCLUSIONS: Our findings suggest that not only the occurrence of MDD but also the severity of anxiety symptoms, may adversely affect the outcome of allergic reactions by favoring the production of cytokines implicated in the pathogenesis of AR and AA, a phenomenon that was attenuated by serotonin.

Assessment of the presence of interleukin 17+ macrophages and Th17 cells in situ in lip and oral tongue cancer.

Increasing clinical evidence indicates that Th17 cells may promote or inhibit tumor progression, however the exact role of these cells in Oral Squamous Cell Carcinoma (OSCCs) pathogenesis and progression remains unclear. Tumor associated macrophages are highly plastic phenotype cells which can differentiate as M1 or M2. The mechanism and cellular phenotype of IL-17 expressing macrophages are unknown. 40 cases of lip and 28 of tongue SCCs were submitted to immunohistochemical analysis, and histologically graded. In tongue cases TNM was analyzed. The number of IL-17+ T cells was higher in lip SCC (p = 0.028). IL-17+ macrophages was greater in tongue SCC (p = 0.014). There were more IL-17+ macrophages in the high-grade malignancy oral tongue SCCs (p = 0.016), yet there was no significant difference in the numbers of RORγt+ lymphocytes by histopathological or TNM analysis. This study provides evidence concerning IL-17's pleiotropic roles, being possibly dependent on its cellular sources in the tumor microenvironment.

Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis.

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara-/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.

Th17/Treg-Related Intracellular Signaling in Patients with Chronic Obstructive Pulmonary Disease: Comparison between Local and Systemic Responses.

Th17/Treg imbalance plays a pivotal role in COPD development and progression. We aimed to assess Th17/Treg-related intracellular signaling at different COPD stages in local and systemic responses. Lung tissue and/or peripheral blood samples were collected and divided into non-obstructed (NOS), COPD stages I and II, and COPD stages III and IV groups. Gene expression of STAT3 and -5, RORγt, Foxp3, interleukin (IL)-6, -17, -10, and TGF-ß was assessed by RT-qPCR. IL-6, -17, -10, and TGF-ß levels were determined by ELISA. We observed increased STAT3, RORγt, Foxp3, IL-6, and TGF-ß gene expression and IL-6 levels in the lungs of COPD I and II patients compared to those of NOS patients. Regarding the systemic response, we observed increased STAT3, RORγt, IL-6, and TGF-ß gene expression in the COPD III and IV group and increased IL-6 levels in the COPD I and II group. STAT5 was increased in COPD III and IV patients, although there was a decrease in Foxp3 expression and IL-10 levels in the COPD I and II and COPD III and IV groups, respectively. We demonstrated that an increase in Th17 intracellular signaling in the lungs precedes this increase in the systemic response, whereas Treg intracellular signaling varies between the compartments analyzed in different COPD stages.

Interleukin-35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis.

Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)- and regulatory B (Breg)-cell induction, helminth infections tend to dampen disease activity. IL-35, the newest member of the IL-12 family, is an inhibitory cytokine composed of an EBI3ß chain subunit, and an IL-12p35 subunit. The aim of this study was to investigate the role of IL-35 during parasite infections occurring in individuals with MS. Numbers of IL-35-producing Breg cells are higher in CSF from helminth-infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL-35 promotes conversion of these cells to Breg cells producing both IL-35 and IL-10. Coculture of B cells from helminth-infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide-specific T cells, as well as production of IFN-γ and IL-17. Following activation, CD4+ CD25+ Treg cells significantly upregulate expression of EBI3 and IL-12p35 mRNA. Furthermore, CD4+ CD25- T cells activated in the presence of IL-35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL-35 Breg cells. These data highlight the important immunoregulatory effects of IL-35 on both Breg and Treg cells, observed in helminth-infected MS subjects.