The impact of IL-10 and IL-17 on myeloid-derived suppressor cells in vitro and in vivo in a murine model of asthma.

Myeloid-derived suppressor cells (MDSCs) hold promise for clinical applications due to their immunosuppressive properties, particularly in the context of inflammation. In the present study, the number and immunosuppressive activity of MDSCs isolated from naïve Il10-/-, Il17-/-, and WT mice as control, as well as from house dust mite extract (HDM)-induced asthmatic Il10-/- and Il17-/- mice, were investigated. IL-10 deficiency increased the number of polymorphonuclear (PMN)-MDSCs in the lung, spleen, and bone marrow, without concurrent impairment of their suppressive activity in vitro. In the asthma model, the IL-17 knockout was concomitant with a lower number and activity of monocytic (M)-MDSCs and an altered inflammatory reaction with impaired lung function. Additionally, we found a higher baseline inflammation of the Il17-/- mice in the lung, manifested in increased airway resistance. We conclude that the impact of IL-10 and IL-17 deficiency on MDSCs differs in the context of inflammation. Accordingly, the in vitro experiments demonstrated an increased number of PMN-MDSCs across tissues in Il10-/- mice, which indicates that IL-10 might serve a pivotal role in preserving immune homeostasis under physiological circumstances. In the context of HDM-induced airway inflammation, IL-17 was found to be an important player in the suppression of pulmonary inflammation and regulation of M-MDSCs.

Impact of local human microbiota on the allergic diseases: Organ-organ interaction.

The homogeneous impact of local dysbiosis on the development of allergic diseases in the same organ has been thoroughly studied. However, much less is known about the heterogeneous influence of dysbiosis within one organ on allergic diseases in other organs. A comprehensive analysis of the current scientific literature revealed that most of the relevant publications focus on only three organs: gut, airways, and skin. Moreover, the interactions appear to be mainly unidirectional, that is, dysbiotic conditions of the gut being associated with allergic diseases of the airways and the skin. Similar to homogeneous interactions, early life appears to be not only a crucial period for the formation of the microbiota in one organ but also for the later development of allergic diseases in other organs. In particular, we were able to identify a number of specific bacterial and fungal species/genera in the intestine that were repeatedly associated in the literature with either increased or decreased allergic diseases of the skin, like atopic dermatitis, or the airways, like allergic rhinitis and asthma. The reported studies indicate that in addition to the composition of the microbiome, also the relative abundance of certain microbial species and the overall diversity are associated with allergic diseases of the corresponding organs. As anticipated for human association studies, the underlying mechanisms of the organ-organ crosstalk could not be clearly resolved yet. Thus, further work, in particular experimental animal studies are required to elucidate the mechanisms linking dysbiotic conditions of one organ to allergic diseases in other organs.

Tumor microenvironment complexity and therapeutic implications at a glance.

The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.

Diabetic lung disease: fact or fiction?

Diabetes mellitus is a chronic, progressive, incompletely understood metabolic disorder whose prevalence has been increasing steadily worldwide. Even though little attention has been paid to lung disorders in the context of diabetes, its prevalence has recently been challenged by newer studies of disease development. In this review, we summarize and discuss the role of diabetes mellitus involved in the progression of pulmonary diseases, with the main focus on pulmonary fibrosis, which represents a chronic and progressive disease with high mortality and limited therapeutic options.

Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis.

RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.

Immune Mechanisms in Pulmonary Fibrosis.

Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, represents a chronic and progressive disease with high mortality and limited therapeutic options. Excessive deposition of extracellular matrix proteins results in fibrotic remodeling, alveolar destruction, and irreversible loss of lung function. Both innate and adaptive immune mechanisms contribute to fibrogenesis at several cellular and noncellular levels. Here, we summarize and discuss the role of immune cells (T cells, neutrophils, macrophages, and fibrocytes) and soluble mediators (cytokines and chemokines) involved in pulmonary fibrosis, pointing toward novel immune-based therapeutic strategies in the field.

The emerging role of myeloid-derived suppressor cells in lung diseases.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterised by their potential to control T-cell responses and to dampen inflammation. While the role of MDSCs in cancer has been studied in depth, our understanding of their relevance for infectious and inflammatory disease conditions has just begun to evolve. Recent studies highlight an emerging and complex role for MDSCs in pulmonary diseases. In this review, we discuss the potential contribution of MDSCs as biomarkers and therapeutic targets in lung diseases, particularly lung cancer, tuberculosis, chronic obstructive pulmonary disease, asthma and cystic fibrosis.

Effects of the flavanone combination hesperetin-naringenin, and orange and grapefruit juices, on airway inflammation and remodeling in a murine asthma model.

We investigated whether flavanones, hesperetin-naringenin, orange, and grapefruit juices reduce airway inflammation and remodeling in murine chronic asthma model. To establish chronic asthma, mice received house dust mite (HDM) for 3 days in 2 weeks, followed by twice per week for 4 weeks. Concurrently, during the last 4 weeks, mice received hesperetin plus naringenin (HN), orange plus grapefruit juice (OGJ), orange juice (OJ), or grapefruit juice (GJ); whereas the asthmatic control (AC) group and non-asthmatic control (NC) group consumed water ad libitum. In histopathological examination, no goblet cells metaplasia was observed in the HN, OJ, and GJ groups; also, intra-alveolar macrophages decreased compared with those of the AC group. Hesperetin plus naringenin significantly decreased subepithelial fibrosis, smooth muscle hypertrophy in airways, and lung atelectasis compared with the AC group. Also, there was a reduction of subepithelial fibrosis in airways in OJ and GJ groups compared with AC group, but it was not noticed in OGJ group. In bronchoalveolar lavage fluid, macrophages numbers decreased in OJ and OGJ groups, whereas eosinophil numbers were increased in OJ group compared with NC group. Our finding revealed that hesperetin plus naringenin ameliorate airway structural remodeling more than orange juice and grapefruit juice in murine model of HDM-induced asthma.

Supplementation of Diabetic Rats with Leucine, Zinc, and Chromium: Effects on Function and Histological Structure of Testes.

The objective was to study whether leucine, zinc, and chromium supplementations influence function and histological structure of testes in a rat model of type 2 diabetes. Seventy seven adult male rats were categorized into 11 groups of 7 animals each: (1) nondiabetic (negative control); (2) non-treated (positive control); (3) treated with insulin; (4) treated with glibenclamide; (5) treated with leucine; (6) treated with zinc; (7) treated with chromium; (8) treated with leucine + zinc; (9) treated with leucine + chromium; (10) treated with zinc + chromium; (11) treated with leucine + zinc + chromium. In the non-treated group, hyperglycemia severely damaged testes morphology as well as the spermatogenic process. Diabetes induction decreased testicular length, height, width, volume, total number of epididymal sperm, and number of live sperm. Seminiferous tubules of diabetic rats showed a decrease in diameter of tubules and height of epithelium. Diabetes induction decreased the number of cells (spermatogonia, spermatocyte, spermatid, and Sertoli) in cross sections of seminiferous tubules. Administration of nutritional supplements to the diabetic rats improved testes morphology and reversed, although not completely, impairment of spermatogenesis. Treatment with nutritional supplements increased testicular length, height, width, and volume. All treatments increased the number of live sperm and the total number of epididymal sperm. Furthermore, nutritional supplements increased diameter of tubules, height of epithelium, and the number of cells in seminiferous tubules. These alleviating effects were more pronounced in animals treated with the leucine-zinc-chromium combination. The present results demonstrate beneficial effects of zinc, leucine, and chromium supplements to improve testes morphology and to restore spermatogenesis in type 2 diabetic rats.

Tiotropium effects on airway inflammatory events in the cat as an animal model for acute cigarette smoke-induced lung inflammation.

BACKGROUND: Chronic obstructive pulmonary disease is an inflammatory lung disease mainly caused by tobacco smoke inhalation. METHODS: Fifteen healthy adult male cats were categorized into 3 groups: (1) control group, (2) exposed to cigarette smoke (CS), and (3) exposed to CS treated with tiotropium. RESULTS: Increases in clinical signs and airway responsiveness in CS cats were found compared to control animals. The airway hyperresponsiveness and clinical signs were significantly attenuated by treatment with tiotropium. The CS-induced pulmonary release of interleukin-6, interleukin-8, monocyte chemotactic protein-1, and tumor necrosis factor alpha was reduced in the tiotropium group. Exposure to CS significantly increased total inflammatory cells number in bronchoalveolar lavage fluid, which was significantly attenuated by treatment with tiotropium. The number of macrophages, eosinophils and neutrophils and lymphocytes was increased after exposure to CS. Tiotropium significantly reduced the number of all these cells. Perivascular, peribronchiolar infiltration of inflammatory cells and Reid index increased in the CS group. Treatment with tiotropium significantly reduced these parameters to control level. Enhanced lipid peroxidation with concomitant reduction of antioxidants status was observed in the CS group. Tiotropium significantly reduced the serum, lung lavage, lung, and tracheal tissue lipid peroxides to near control levels. Tiotropium also decreased lung and tracheal protein leakage, and prevented the reduction of total antioxidant status in serum, lung lavage, lung and tracheal tissue of the CS group. CONCLUSION: Cigarette smoke increases airway responsiveness and inflammation in a cat model of CS induced lung inflammation. It can effectively be reduced by treatment with tiotropium.

Myeloid-derived suppressor cells in influenza virus-induced asthma exacerbation.

Myeloid-derived suppressor cells (MDSCs) are a phenotypically heterogenous group of cells that potently suppress the immune response. A growing body of evidence supports the important role of MDSCs in a variety of lung diseases, such as asthma. However, the role of MDSCs in asthma exacerbation has so far not been investigated. Here, we studied the role of MDSCs in a murine model of influenza virus-induced asthma exacerbation. BALB/c mice were exposed to house dust mite (HDM) three times a week for a total of five weeks to induce a chronic asthmatic phenotype, which was exacerbated by additional exposure to the A/Hamburg/5/2009 hemagglutinin 1 neuraminidase 1 (H1N1) influenza virus. Induction of lung inflammatory features, production of T helper (Th) 1- and Th2- associated inflammatory cytokines in the lavage fluid and an increased airway hyper-responsiveness were observed, establishing the asthma exacerbation model. The number and activity of pulmonary M-MDSCs increased in exacerbated asthmatic mice compared to non-exacerbated asthmatic mice. Furthermore, depletion of MDSCs aggravated airway hyper-responsiveness in exacerbated asthmatic mice. These findings further denote the role of MDSCs in asthma and provide some of the first evidence supporting a potential important role of MDSCs in asthma exacerbation.

The role of PGE2 and EP receptors on lung's immune and structural cells; possibilities for future asthma therapy.

Asthma is the most common airway chronic disease with treatments aimed mainly to control the symptoms. Adrenergic receptor agonists, corticosteroids and anti-leukotrienes have been used for decades, and the development of more targeted asthma treatments, known as biological therapies, were only recently established. However, due to the complexity of asthma and the limited efficacy as well as the side effects of available treatments, there is an urgent need for a new generation of asthma therapies. The anti-inflammatory and bronchodilatory effects of prostaglandin E2 in asthma are promising, yet complicated by undesirable side effects, such as cough and airway irritation. In this review, we summarize the most important literature on the role of all four E prostanoid (EP) receptors on the lung's immune and structural cells to further dissect the relevance of EP2/EP4 receptors as potential targets for future asthma therapy.

Intranasal EP4 agonist and arginase-1 therapy in a murine model of asthma.

Research findings evermore suggest a crucial role of myeloid-derived suppressor cells (MDSCs) in chronic lung diseases including asthma. Previously, we showed that intravenous (IV) treatment with a prostaglandin E2 receptor 4 (EP4) agonist, L-902,688, promoted MDSC suppressive activity. IV therapy with L-902,688 and BCT-100, a human pegylated arginase-1, ameliorated lung inflammatory features in a murine model of asthma. Here, we further investigate the potential therapeutic approach by studying the local therapy effects on the lungs after intranasal (IN) application. Using a two-week model of house dust mite (HDM)-induced murine asthma, the effect of IN treatment with L-902,688 or BCT-100 on in vivo lung function, inflammatory features of asthma and MDSC generation and activation was studied. Our experiments demonstrated increased suppressive activity of pulmonary MDSCs after induction of allergic airway disease. IN treatment with L-902,688 and BCT-100 further enhanced the immunosuppressive activity of pulmonary MDSCs. Additionally, treatment with BCT-100 reduced pulmonary T cell numbers. Asthmatic mice that received IN L-902,688 showed improved in vivo lung function. In conclusion, our results underline the potential of modulating MDSCs systemically or locally as a future therapeutic option in airway inflammatory diseases such as asthma.

Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine.

Generation of functional transcripts requires transcriptional initiation at regular start sites, avoiding production of aberrant and potentially hazardous aberrant RNAs. The mechanisms maintaining transcriptional fidelity and the impact of spurious transcripts on cellular physiology and organ function have not been fully elucidated. Here we show that TET3, which successively oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other derivatives, prevents aberrant intragenic entry of RNA polymerase II pSer5 into highly expressed genes of airway smooth muscle cells, assuring faithful transcriptional initiation at canonical start sites. Loss of TET3-dependent 5hmC production in SMCs results in accumulation of spurious transcripts, which stimulate the endosomal nucleic-acid-sensing TLR7/8 signaling pathway, thereby provoking massive inflammation and airway remodeling resembling human bronchial asthma. Furthermore, we found that 5hmC levels are substantially lower in human asthma airways compared with control samples. Suppression of spurious transcription might be important to prevent chronic inflammation in asthma.

Antiemetic efficacy of promethazine on xylazine-induced emesis in cats.

The prophylactic antiemetic effect of 3 dosages of promethazine injected into cats 1 h before administration of xylazine was compared with that of a saline solution. Prior treatment with 2 and 4 mg/kg of promethazine significantly reduced the frequency of emetic episodes. Promethazine may be used as a prophylactic antiemetic in cats treated with xylazine.

Pharmacological modulation of myeloid-derived suppressor cells to dampen inflammation.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population with potent suppressive and regulative properties. MDSCs' strong immunosuppressive potential creates new possibilities to treat chronic inflammation and autoimmune diseases or induce tolerance towards transplantation. Here, we summarize and critically discuss different pharmacological approaches which modulate the generation, activation, and recruitment of MDSCs in vitro and in vivo, and their potential role in future immunosuppressive therapy.

Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

Myeloid-Derived Suppressor Cells Dampen Airway Inflammation Through Prostaglandin E2 Receptor 4.

Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through cyclooxygenase-2 and arginase-1 pathways. Here, we further dissected this mechanism by studying the role and therapeutic relevance of the downstream mediator prostaglandin E2 receptor 4 (EP4) in a murine model of asthma. We adoptively transferred MDSCs generated using an EP4 agonist in a murine model of asthma and studied the consequences on airway inflammation. Furthermore, pegylated human arginase-1 was used to model MDSC effector activities. We demonstrate that the selective EP4 agonist L-902,688 increased the number and suppressive activity of MDSCs through arginase-1 and nitric oxide synthase-2. These results showed that adoptive transfer of EP4-primed MDSCs, EP4 agonism alone or arginase-1 administration ameliorated lung inflammatory responses and histopathological changes in asthmatic mice. Collectively, our results provide evidence that MDSCs dampen airway inflammation in murine asthma through a mechanism involving EP4.

The impact of microRNAs on myeloid-derived suppressor cells in cancer.

Inflammation promotes cancer development. To a large extent, this can be attributed to the recruitment of myeloid-derived suppressor cells (MDSCs) to tumors. These cells are known for establishing an immunosuppressive tumor microenvironment by suppressing T cell activities. However, MDSCs also promote metastasis and angiogenesis. Critically, as small non-coding RNAs that regulate gene expression, microRNAs (miRNAs) control MDSC activities. In this review, we discuss how miRNA networks regulate key MDSC signaling pathways, how they shape MDSC development, differentiation and activation, and how this impacts tumor development. By targeting the expression of miRNAs in MDSCs, we can alter their main signaling pathways. In turn, this can compromise their ability to promote multiple hallmarks of cancer. Therefore, this may represent a new powerful strategy for cancer immunotherapy.

Rapamycin delays allograft rejection in obese graft recipients through induction of myeloid-derived suppressor cells.

Obesity has become a relevant problem in transplantation medicine with steadily increasing numbers of obese graft recipients. However, the effect of immunomodulatory drugs on transplant-related outcomes among obese patients are unknown. Therefore, we evaluated the impact of rapamycin on allograft rejection and alloimmune response in a murine model of diet-induced obesity and fully-mismatched skin transplantation. Rapamycin significantly delayed allograft rejection in obese recipient mice compared to treated lean mice (14.5 days vs. 10.7 days, p = 0.005). Treatment with rapamycin increased frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs), augmented the immunosuppressive activity of M-MDSCs on T cells through indoleamine 2,3-dioxygenase pathway and shifted CD4+T cells towards regulatory T cells in obese graft recipients. In summary, our results demonstrate that rapamycin delays allograft rejection in obese graft recipients by enhancing suppressive immune cell function and shifting immune cell subsets towards anti-inflammatory conditions.