The TGF-beta-Pseudoreceptor BAMBI is strongly expressed in COPD lungs and regulated by nontypeable Haemophilus influenzae

Drömann, Daniel; Rupp, Jan; Rohmann, K; Osbahr, Sinia; Ulmer, Artur J.; Marwitz, Sebastian; Röschmann, Kristina; Abdullah, Mahdi; Schultz, Holger; Vollmer, Ekkehard; Zabel, P.; Dalhoff, K; Goldmann, Torsten

doi:10.1186/1465-9921-11-67

Cited by 48 publications

(47 citation statements)

References 32 publications

(38 reference statements)

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“…In the context of lung disease, the overexpression of BAMBI has been observed in the tissues of COPD patients and hypothesized to control local inflammation and remodeling processes (10). The expression of BAMBI at high levels has also been detected in colorectal cancer (11) and ovarian cancer (12) and has been linked to metastasis in colorectal cancer (13).…”

Section: Introductionmentioning

confidence: 94%

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

et al. 2016

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Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGFb elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGFb signaling pathway. Alterations of epithelialto-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGFb pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGFb-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGFb signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785-801. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 94%

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

et al. 2016

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“…The costimulatory molecule CD161 is a key expression marker for MAIT cells, which can recognize the ligand lectin-like transcript 1 (LLT1) expressed by respiratory epithelial cells in response to infection and proinflammatory cytokines (48). H. influenzae can invade the lung tissue (49,50) and enter respiratory epithelial cells and macrophages in chronic bronchitis (6)(7)(8)51). Exacerbations of chronic bronchitis are associated with an increase in the presence of NTHi bacteria inside epithelial cells as seen in 33 to 87% of biopsies (6,8).…”

Section: Cd161mentioning

confidence: 99%

Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection

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Wallington²,

Williams

et al. 2016

Am J Respir Crit Care Med

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Rationale: Mucosal-associated invariant T (MAIT) cells are a recently described abundant, proinflammatory T-cell subset with unknown roles in pulmonary immunity. Nontypeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during chronic obstructive pulmonary disease (COPD) exacerbations and is a plausible target for MAIT cells.Objectives: To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD.Methods: Eleven subjects with COPD receiving ICS, 8 steroid-naive subjects with COPD, and 21 healthy control subjects underwent phlebotomy, sputum induction, bronchoalveolar lavage, and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi.Measurements and Main Results: Frequencies of Va7.2 1 CD161 1 MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-g expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICStreated subjects with COPD (median 0.38%; interquartile range [IQR], 0.25-0.96) compared with healthy control subjects (1.8%; IQR, 1.4-2.5; P = 0.001) or steroid-naive patients with COPD (1.8%; IQR, 1.2-2.3; P = 0.04). MAIT cells were reduced in bronchial biopsies from subjects with COPD treated with steroids (0.73%; IQR, 0.46-1.3) compared with healthy control subjects (4.0%; IQR, 1.6-5.0; P = 0.02). Coculture of live NTHi increased macrophage surface expression of MR1 and induced IFN-g from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-g-positive frequencies, 2.9, 8.6, and 27.6%, respectively). In vitro fluticasone and budesonide reduced MR1 surface expression twofold and decreased NTHi-induced IFN-g secretion eightfold.Conclusions: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naive, COPD. NTHi constitutes a target for pulmonary MAIT-cell immune responses, which are significantly impaired by corticosteroids.

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“…Particular aspects of infections with the pathogens Chlamydophila pneumoniae, Streptococcus pneumoniae, and Haemophilus influenzae were analyzed in similar systems (28,39,40). Although certain characteristics of HLTEs may depend on clinical parameters, the patients' medical conditions, and donor diversity, we obtained statistically robust, reproducible results.…”

Section: Discussionmentioning

confidence: 73%

“…Tumor-free pulmonary tissue samples of approximately 1 cm 3 were obtained from surgery patients as described previously (28). Samples were infected with the respective L. pneumophila strain and incubated at 37°C and 5% CO 2 for up to 48 h. Microscopic inspection of untreated samples at different time points ensured tissue vitality (see below).…”

Section: Methodsmentioning

confidence: 99%

Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

et al. 2014

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Histopathologically, Legionnaires' disease, caused by the Gram-negative bacterium Legionella pneumophila, is an acute fibrinopurulent pneumonia. Since the first documented outbreak of Legionnaires' disease in 1976, several autopsy series have been published (1). Samples from patients who died from L. pneumophila pneumonia exhibit a massive infiltration of neutrophils and macrophages into the alveoli and destruction of alveolar septa. Moreover, the alveolar epithelium shows sloughs, and inflammatory cells exhibit intense necrosis. L. pneumophila is present mainly in alveoli and tends to cluster inside macrophages. In late infection stages, bacteria disseminate to the patient's spleen, kidneys, bone marrow, and lymph nodes (1-4).Different models have been established to analyze specific aspects of infection. Besides human monocellular systems such as macrophages and epithelial cells, protozoa such as Acanthamoeba castellanii, Hartmannella vermiformis, and Dictyostelium discoideum were used to study the cellular and molecular pathogenicity of L. pneumophila (5-9). These studies revealed that L. pneumophila primarily enters phagocytes and resides within a unique membrane-bound compartment termed the Legionellacontaining vacuole (LCV). The establishment of this replication niche requires the translocation of about 300 effector proteins into the host cell via a functional Dot/Icm type IV secretion (10-12). Studying transcriptional responses of L. pneumophila-infected macrophages and D. discoideum vegetative cells also shed light on the cellular mechanisms of Legionnaires' disease (13-16). Moreover, proteomic approaches were shown to be powerful tools to characterize both sides of the host-pathogen interaction (17)(18)(19). Mammalian models such as guinea pigs, mice, rhesus monkeys, and marmosets were used to address immunological, pathological, and pharmacological questions (20)(21)(22). Despite providing enormous progress in the knowledge about mechanisms of L. pneumophila infections, each of the current infection models has intrinsic limitations. Cell culture assays lack the complex interaction networks between the specialized cell types and extracellular components in the human lung. Guinea pig infections require intraperitoneal or intratracheal inoculation techniques, and owing to a different genetic and immunological background, the adequacy and transferability to humans can be questioned.Given the different model-immanent limitations, numerous intra-and extracellular interactions of L. pneumophila factors with human lung tissue structures remain unknown. For example, early infection events appear to be underexplored, since histopathology studies were performed postmortem. Even conspicuous subcellular structures, such as the abundant outer membrane vesicles (OMVs) shed by L. pneumophila, have not yet been investigated in human lung tissue. OMVs contain large amounts of degradative enzymes and other virulence-related proteins, which

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The TGF-beta-Pseudoreceptor BAMBI is strongly expressed in COPD lungs and regulated by nontypeable Haemophilus influenzae

Cited by 48 publications

References 32 publications

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection

Human Lung Tissue Explants Reveal Novel Interactions during Legionella pneumophila Infections

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