Immunomodulatory Activity of Flagellin on Human Respiratory Epithelium
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE304065 | GEO | 2026/08/24
REPOSITORIES: GEO
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Project description:The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense, enabling the airway surface to recognize and respond to a variety of insults in inhaled air. Based on the knowledge that smokers are more susceptible to pulmonary infection and the airway epithelium of smokers with chronic obstructive pulmonary disease (COPD) is characterized by bacterial colonization and acute exacerbation of airway infections, we assessed whether smoking alters the expression of TLRs in human small airway epithelium, the primary site of smoking-induced disease. Microarrays were used to survey the TLR family gene expression in small airway (10th-12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in ≥50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most strikingly changed gene is TLR5, which down-regulated in healthy smokers (1.4-fold decrease, p<10-13) and in smokers with COPD (1.6-fold, p<10-14). TaqMan RT-PCR confirmed these observations. Bronchial biopsies immunofluorescence showed that TLR5 protein was expressed mainly on the apical side of the human airway epithelium and decreased in healthy smokers and smokers with COPD. In vitro studies showed that the level of TLR5 downstream genes, IL-6 and IL-8 were highly induced in TLR5 high-expressing cells compared to TLR5 low-expressing cells after flagellin exposure. In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 likely contributes to smoking-related susceptibility to airway infection. The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense. Microarrays were used to survey the TLR family gene expression in small airway (10th-12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in ≥50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most strikingly changed gene is TLR5, which down-regulated in healthy smokers (1.4-fold decrease, p<10-13) and in smokers with COPD (1.6-fold, p<10-14). In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 likely contributes to smoking-related susceptibility to airway infection. *** Processed data not provided for all gene expression records. ***
2012-10-03 | E-GEOD-30063 | biostudies-arrayexpress
Project description:Antibiotic-resistant respiratory infections can lead to treatment failure, highlighting the need for alternative strategies. FLAMOD, a recombinant flagellin and Toll-like receptor 5 agonist, stimulates innate immunity when delivered intranasally. In mouse models, FLAMOD is effective against bacterial pneumonia. The protective efficacy was associated with activation of airway epithelial cells. This study aimed to assess the tolerance of human primary respiratory epithelium to FLAMOD administered apically as liquid droplets or by nebulization, to measure the FLAMOD-mediated innate immune response, and to analyze the pharmacokinetics of FLAMOD. We used epithelia reconstituted from human nasal and bronchial (MucilAir™), small airways (SmallAir™) and alveolar (AlveolAir™) primary epithelial cells, cultured at the air-liquid interface. We report that daily administration of escalating doses of FLAMOD for 5 days was well tolerated in the various epithelium as epithelial integrity, cilia motion and viability were not affected. FLAMOD was rapidly degraded and leakage into the basal compartment was not detected. An immunomodulatory effect was identified in each epithelium, and found to be FLAMOD dose-dependent with an effective dose in the picomolar range. Similar safety profile and immune responses were obtained with airway epithelium from cystic fibrosis and chronic obstructive pulmonary disease patients. In conclusion, this study supports the development of the use of TLR5 agonist for respiratory delivery to stimulate innate defenses against infections of vulnerable patients.
2026-08-24 | GSE313945 | GEO
Project description:The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense, enabling the airway surface to recognize and respond to a variety of insults in inhaled air. Based on the knowledge that smokers are more susceptible to pulmonary infection and the airway epithelium of smokers with chronic obstructive pulmonary disease (COPD) is characterized by bacterial colonization and acute exacerbation of airway infections, we assessed whether smoking alters the expression of TLRs in human small airway epithelium, the primary site of smoking-induced disease. Microarrays were used to survey the TLR family gene expression in small airway (10th-12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in ≥50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most strikingly changed gene is TLR5, which down-regulated in healthy smokers (1.4-fold decrease, p<10-13) and in smokers with COPD (1.6-fold, p<10-14). TaqMan RT-PCR confirmed these observations. Bronchial biopsies immunofluorescence showed that TLR5 protein was expressed mainly on the apical side of the human airway epithelium and decreased in healthy smokers and smokers with COPD. In vitro studies showed that the level of TLR5 downstream genes, IL-6 and IL-8 were highly induced in TLR5 high-expressing cells compared to TLR5 low-expressing cells after flagellin exposure. In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 likely contributes to smoking-related susceptibility to airway infection.
2012-10-03 | GSE30063 | GEO
Project description:The activity of the potent nasal adjuvant flagellin depends on initial activation of airway epithelilal cells. This study aims at investigating the immune cells involved in the antigen presentation within the respiratory tract. First, microarrays characterized that activation/recruitment of immune cells was the main signature of flagellin activation in lung. Neutrophils and classical monocytes were strongly recruited into the lungs and take up antigen upon nasal administration of flagellin. In contrast, the numbers of lung CD11b+ or CD103+ DC and alveolar macrophages were not enhanced although these cells were very efficient in antigen uptake. Our experiments showed that CD11b+ DC but not monocytes, PMN, CD103+ DC are not essential for the adjuvant effect. Flagellin signaling enhanced the functional activation of lung CD11b+ conventional DC and their migration to the lymph nodes. Using Cd11c-DTR mice, CD11b+ DC from lymph nodes were identified as the major stimulators of CD4 T cell activation. Finally, the migration and maturation of mucosal DC was independent of direct signaling, highlighting the contribution of epithelial factors in the mucosal adjuvant effect of flagellin. In conclusion, these data demonstrate that adjuvant activity can be dissociated from inflammatory cell recruitment an open new perpectives for improvement of vaccines. Female C57BL/6J (6 weeks old) mice were immunized with the TLR5 agonist Flagellin (1μg diluted in PBS) by intranasal (i.n.) administration. Blood samples of four time points post immunization were taken at 2h, 4h, 18h and 48h. Microarray experiments were performed as single-color hybridizations.
2014-01-01 | E-GEOD-46421 | biostudies-arrayexpress
Project description:Microarray analysis of IECs from Tlr5+/+ and Tlr5–/– mice stimulated with either medium alone or flagellin (1 µg/ml); to elucidate TLR5-mediated immune responses in IECs. Keywords: ordered
2006-08-01 | GSE5112 | GEO
Project description:Microarray analysis of IECs from Tlr5+/+ and Tlr5-/- mice stimulated with either medium alone or flagellin (1 µg/ml); to elucidate TLR5-mediated immune responses in CD11c+ LPCs Keywords: ordered
2006-08-01 | GSE5113 | GEO
Project description:The purpose of the study is to compare the transcriptomic profile of the airway epithelial cell line Calu-3 in reponse to Pseudomonas aeruginosa virulence factor flagellin. CF is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR gene in Calu-3 cells was knockdown by CRISPR-Cas9 (TS) and a control cell line (CTL) was aslo generated using a non-targeting guide RNA. CTL and CFTR KD Calu3-cells were grown on Transwell filters, polarized at the air-liquid interface and exposed to flagellin for 6 hours. We considered 2 non-stimulated (ND) conditions: CTL-NS and TS-NS, and 2 conditions stimulated with flagellin (Flag): CTL-Flag and TS-Flag.
2020-08-24 | GSE133495 | GEO
Project description:Airway epithelial cells represent the first line of defense against respiratory pathogens. Flagellin drives the motility of many mucosal pathogens and has been suggested as an immune enhancing adjunctive therapeutic in infections of the airways. This study leveraged single-cell RNA sequencing to determine cell-specific effects of flagellin in primary human bronchial epithelial cells growing in air-liquid interface. Seven cell clusters were identified, including ciliated cells, ionocytes and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells demonstrated a proportional increase in response to flagellin. Inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, whilst in inflammatory basal cells transcriptome profiles indicated enhanced oxidative phosphorylation. Inhibition of mTOR prevented the shift to glycolysis and reduced inflammatory gene transcription specifically in inflammatory secretory cells. This data demonstrates the functional heterogeneity of the human airway epithelium upon exposure to flagellin.
2024-09-18 | GSE272188 | GEO
Project description:The COVID-19 pandemic has revealed differences in individual susceptibility and severity, with pre-existing respiratory diseases as potential risk factors. Using an in vitro model of differentiated primary bronchial epithelial cells, we investigated the molecular mechanisms of SARS-CoV-2 infection in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Our study found that CF and COPD airway epithelium had reduced susceptibility to SARS-CoV-2 compared to healthy controls. This was linked to preserved epithelial integrity, lower viral replication, and attenuated antiviral and inflammatory responses. Mechanistically, we identified reduced TMPRSS2 activity as a contributing factor in CF epithelium. Importantly, the baseline upregulation of complement and inflammatory pathways in CF and COPD epithelium appeared to prime an antiviral state prior to infection. Analysis of a COVID-19 patient cohort validated our findings, showing correlations between specific inflammatory markers (CXCL-10, SERPINA1, and CFB) and SARS-CoV-2 infection severity. This study offers insights into SARS-CoV-2 pathogenesis and potential biomarkers for clinical monitoring.
2025-02-12 | PXD055635 | Pride
Project description:Vaccine adjuvants enhance adaptive immunity to co-administered antigens. Whereas the modes of action are multiple, the activation of antigen-presenting cells (APC) like dendritic cells by adjuvants is a prerequisite. Detection of microbial signals by innate sensors like Toll-like receptors (TLR) is a major mechanism of APC activation. Most candidate or licensed vaccines assume that adjuvant activity of TLR agonists depends on direct effect on APCs. This study addressed whether TLR stimulation of non-hematopoietic cells could contribute to the adjuvant effect. Nasal administration of flagellin enhanced T cell- and antibody-mediated immunity to co-administered antigens in a TLR5-dependent but inflammasome-independent manner. We found that lung radioresistant cells were sufficient to promote immunity, thereby suggesting that direct TLR5-mediated APC stimulation is dispensable to adjuvant activity. Consistent with this, radioresistant compartment is essential to stimulate the swift TLR5-dependent transcription. The transcriptional response was restricted to the epithelial compartment and was associated to the production of a narrow set of mediators including the chemokine CCL20, known to promote APC recruitment in mucosal tissues. Besides, flagellin was rapidly degraded in lower airways and was not transported into lung parenchyma or peripheral tissues. This study therefore suggests an unexpected mechanism for how TLR agonists act as adjuvant and how epithelium is instrumental to sense and integrate microbial signals to promote adaptive immunity. In conclusion, the immune-enhancing effect of adjuvants on epithelial cells can be harnessed for improving vaccines. 1 µg of flagellin was instillated intranasally to LPS-unresponsive C3H/HeJ mice. Total lung RNA was extracted 1h later and prepare for hybridization on Affymetrix microarrays.
2013-03-22 | E-GEOD-45369 | biostudies-arrayexpress