Myeloid RelA regulates pulmonary host defense networks

Hess, C.; Herr, Christian; Beißwenger, Christoph; Zakharkina, Tetyana; Schmid, RM; Bals, Robert

doi:10.1183/09031936.00196408

Cited by 28 publications

(32 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies showed that TLR3 is expressed in primary respiratory epithelial cells and that TLR3 stimulation activates the IFN-b signaling pathways (34). We used Aspergillus extract instead of hyphae and conidia in our study and found that IFN-b signaling plays an important role as a target in the mechanism of IP-10 suppression by Aspergillus extract.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Epithelial Signal Transducer and Activator of Transcription 1 Activation by Extracts of Aspergillus fumigatus

Bhushan

Homma

Norton

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Aspergillus fumigatus (AF) is often pathogenic in immune-deficient individuals and can cause life-threatening infections such as invasive aspergillosis. The pulmonary epithelial response to AF infection and the signaling pathways associated with it have not been completely studied. BEAS-2B cells or primary human bronchial epithelial cells were exposed to extracts of AF and challenged with IFN-b or the Toll-like receptor 3 agonist double-stranded RNA (dsRNA). Cytokine release (B-cell activating factor of the TNF family [BAFF], IFN-g-induced protein-10 [IP-10], etc.) was assessed. AF extract was separated into low-molecular-weight (LMW) and highmolecular-weight (HMW) fractions using ultra 4 centrifugal force filters to characterize the activity. Real-time PCR was performed with a TaqMan method, and protein estimation was performed using ELISA techniques. Western blot was performed to assess phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-b and dsRNA induced messenger RNA (mRNA) expression of BAFF (350-and 452-fold, respectively [n = 3]) and IP-10 (1,081-and 3,044-fold, respectively [n = 3]) in BEAS-2B cells. When cells were pretreated with AF extract for 1 hour and then stimulated with IFN-b or dsRNA for 6 hours, induction of BAFF and IP-10 mRNA was strongly suppressed relative to levels produced by IFN-b and dsRNA alone. When compared with control, soluble BAFF and IP-10 protein levels were maximally suppressed in dsRNA-stimulated wells treated with 1:320 wt/vol AF extract (P , 0.005). Upon molecular size fractionation, a LMW fraction of AF extract had no measurable suppressive effect on IP-10 mRNA expression. However, a HMW fraction of the AF extract significantly suppressed IP-10 expression in BEAS-2B cells that were stimulated with dsRNA or IFN-b. When BEAS-2B cells were pretreated with AF extract and then stimulated with IFN-b, reduced levels of pSTAT1 were observed, with maximum suppression at 4 and 6 hours. Our results show that AF extracts suppressed expression of inflammatory cytokines in association with inhibition of the IFN-b signaling pathway and suppression of the formation of pSTAT1. Clinical RelevanceThe components of Aspergillus fumigatus extract that inhibit JAK-signal transducer and activator of transcription 1 (STAT1) signaling could impair antiviral immunity and could also contribute to the skewing of adaptive immune responses toward T helper (Th) 2 observed in Aspergillus-infected individuals by undermining the Th1 responses via inhibition of the activation of STAT1. We believe that the inhibitory effect on STAT1 activation could be exploited for beneficial effects once we better understand the identity of the factor and the molecular mechanism by which STAT1 phosphorylation is inhibited.

show abstract

Section: Discussionmentioning

confidence: 99%

Suppression of Epithelial Signal Transducer and Activator of Transcription 1 Activation by Extracts of Aspergillus fumigatus

Bhushan

Homma

Norton

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…The protocol was approved by the Institutional Review Board (ethics committee) of the Saarland University Hospital, and informed consent was obtained from the patients. Lungs of mice were embedded in paraffin, and immunohistochemistry was performed as described earlier (2). FOXO3 was detected with primary Abs (anti-FOXO3A; Abcam) diluted 1:200 in TBS (13 PBS [pH 7.2], 0.1% BSA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Some of these functions are constitutively active. However, in case of infection, epithelial cells directly detect pathogen-associated molecular patterns (PAMPs) in a pattern recognition receptor-dependent manner, resulting in enhanced innate immune responses (2,3,5). In addition, inflammatory cytokines (e.g., IL-1b and IL-17) released by professional immune cells induce innate immune functions of airway epithelial cells (6,7).…”

mentioning

confidence: 99%

“…In the lung, resident myeloid cells (e.g., alveolar macrophages) and respiratory epithelial cells are principle components of the innate host immunity required to prevent bacterial colonization and infection as well as to initiate adaptive immunity (1,2). Innate immune functions of alveolar and airway epithelial cells include formation of mechanical barriers, production of mucus, mucociliary clearance, secretion of antimicrobial factors and peptides, and recruitment of professional immune cells by cytokine release (1,3,4).…”

mentioning

confidence: 99%

See 1 more Smart Citation

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Seiler

Hellberg

Lepper

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. Forkhead box transcription factor family O (FOXO) transcription factors are key regulators of cellular metabolism, proliferation, and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells. We show that bacterial pathogens potently activate FOXO transcription factors in cultured human respiratory epithelial cells in vitro. Infection of mice with bacterial pathogens resulted in the activation of FOXO transcription factors in alveolar and bronchial epithelial cells in vivo. Active FOXO was also detectable in human bronchial tissue obtained from subjects with different infection-related lung diseases. Small interfering RNA–mediated knockdown of FOXO in bronchial epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines, both under basal conditions and upon infection. FOXO deficiency further affected internalization of Haemophilus influenzae in bronchial epithelial cells. Finally, we show that TLR3 activates innate immune responses in a FOXO-dependent manner. In conclusion, FOXO transcription factors are involved in the cellular responses to bacterial stimuli and act as central regulators of innate immune functions in respiratory epithelial cells.

show abstract

“…However, in recent years, it has become evident that the epithelial surface of the respiratory tract not only provides a physical barrier that is highly effective in blocking penetration by most microbes but also has the ability to recognise microbes and to initiate an immune response [8,9]. Similar to classical immune cells, such as macrophages or neutrophils, respiratory epithelial cells are known to express a variety of pattern recognition receptors, including TLRs and NOD-like receptors (nuclear oligomerisation domain), allowing for the detection of diverse AFFILIATIONS *Dept of Internal Medicine, Division for Pulmonary Diseases, Universitätsklinikum des Saarlandes, Homburg, pathogens, such as bacteria and viruses [10]. Even though innate immune functions of respiratory epithelial cells are well described in the response to bacteria and viruses, little is known about the response of these cells to fungal pathogens such as A. fumigatus and its spores, the conidia.…”

mentioning

confidence: 99%

Aspergillus fumigatusconidia induce interferon-β signalling in respiratory epithelial cells

Beißwenger¹,

Hess²,

Bals³

2011

Eur Respir J

Self Cite

View full text Add to dashboard Cite

Aspergillus fumigatus is a fungal pathogen of major clinical importance. However, little is known about the role of human bronchial epithelial cells (HBECs) during A. fumigatus conidia induced inflammation.Here, we show that differentiated respiratory epithelial cells recognise inactivated resting conidia but not swollen conidia or hyphae, resulting in the induction of the interferon (IFN)-b signalling pathway and the expression of IFN-b-inducible genes, such as IFN-c-inducible protein (IP)-10. This induction was internalisation dependent.We identified double-stranded conidial RNA recognised by Toll-like receptor-3 as a factor responsible for the expression of IFN-b and IP-10. Inhibition of receptor-interacting protein-1/ TANK-binding kinase-1, known to mediate IFN-b signalling, was sufficient to inhibit the induction of IFN-b and IP-10 expression by conidia. Even though conidia induced the activation of nuclear factor (NF)-kB in HBECs, IP-10 expression was only partially dependent on NF-kB signalling.These results provide evidence that respiratory cells are activated by the double-stranded RNA of resting conidia and initiate a first immune response to inhaled conidia in an IFN-b-dependent manner.

show abstract

Myeloid RelA regulates pulmonary host defense networks

Cited by 28 publications

References 44 publications

Suppression of Epithelial Signal Transducer and Activator of Transcription 1 Activation by Extracts of Aspergillus fumigatus

Suppression of Epithelial Signal Transducer and Activator of Transcription 1 Activation by Extracts of Aspergillus fumigatus

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Aspergillus fumigatusconidia induce interferon-β signalling in respiratory epithelial cells

Contact Info

Product

Resources

About