RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

Arikkatt, Jaisy; Ullah, Ashik; Short, Kirsty R.; Zhang, Vivian; Gan, Wan Jun; Loh, Zhixuan; Werder, Rhiannon B.; Simpson, Jennifer; Sly, Peter D.; Mazzone, Stuart B.; Spann, Kirsten; Ferreira, Manuel; Upham, John W.; Sukkar, Maria B.; Phipps, Simon

doi:10.7554/elife.21199

Cited by 24 publications

(32 citation statements)

References 53 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 70 We are currently testing this possibility using mouse models of experimental asthma. Various models have been described, 120 including those that mimic mechanisms underlying acute allergic asthma; 121 , 122 chronic asthma; 123 and viral-induced asthma 124 in humans. It is not always straightforward to decide which model is most appropriate to use, and different models can result in different findings, 100 presumably because of the different underlying pathophysiology.…”

Section: Opportunities and Challengesmentioning

confidence: 99%

Lessons from ten years of genome‐wide association studies of asthma

2017

View full text Add to dashboard Cite

Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10−8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development.

show abstract

Section: Opportunities and Challengesmentioning

confidence: 99%

Lessons from ten years of genome‐wide association studies of asthma

2017

View full text Add to dashboard Cite

show abstract

“…Consistent with this theory, IL-2/IL-33-stimulated ILC2s produced IL-13 in a biphasic manner, with the second phase occurring after the peak of HMGB1 release (Fig 6B). As we had previously shown that RAGE -/mice generate attenuated type-2 inflammatory responses to both viral-or allergen-triggered experimental asthma [6,37], we speculated that HMGB1/RAGE ligation promotes type-2 cytokine production by ILC2s. To determine whether ILC2s express RAGE, we used RAGE -/mice in which the functional Ager gene has been replaced by GFP.…”

Section: Ilc2-derived Hmgb1 In Irf7 -/Mice Acts In An Autocrine Mannementioning

confidence: 89%

“…Asthma is a polygenic disorder, underpinned by gene-environment interactions. As individual SNP effects on disease risk are small, we elected to use knockout mice, which we have used previously to identify novel pathogenic mechanisms [34,37,47]. We believe this approach is preferable to using an extremely high inoculum in WT mice that can induce non-physiological responses and increase the potential for false positives.…”

Section: Plos Pathogensmentioning

confidence: 99%

HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling

et al. 2020

Self Cite

View full text Add to dashboard Cite

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain illdefined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling.

show abstract

“…Moving toward the plasma membrane, HMGB1 binds RAGE, a receptor also expressed in epithelial cell cultures ( 28 ) and able to exacerbate RSV disease by amplifying the expression of proinflammatory agents. RAGE deficiency has been associated with viral-induced asthma phenotype in a mouse model ( 29 ). Our data also confirmed nuclear HMGB1 localization during the early phase of infection, which has been shown to be a critical initial event for an efficient viral cycle ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

Induction of high-mobility group Box-1 in vitro and in vivo by respiratory syncytial virus

et al. 2018

View full text Add to dashboard Cite

Background Despite decades have passed since its discovery, accurate biomarkers of Respiratory syncytial virus (RSV) disease activity and effective therapeutic strategies are still lacking. The high mobility group box type 1 (HMGB1) protein has been proposed as a possible link between RSV and immune system, but only limited information is currently available to support this hypothesis. Methods Expression of HMGB1 gene and protein were analyzed by quantitative PCR, ELISA, Western blot, immunocytochemistry, and confocal microscopy in immortalized and primary human bronchial epithelial cells, as well as in rat pup lungs. The role of HMGB1 in RSV infection was explored using glycyrrhizin, a selective HMGB1 inhibitor. Results RSV infection strongly induced HMGB1 expression both in vitro and in vivo. Glycyrrhizin dose-dependently inhibited HMGB1 upregulation in both RSV-infected immortalized and primary human bronchial epithelial cells, and this effect was associated with significant reduction of viral replication. Conclusions Our data suggest that HMGB1 expression increases during RSV replication. This seems to play a critical pathogenic role as its selective inhibition virtually modified the infection. These observations provide further insight into the pathophysiology of RSV infection and uncover a potential biomarker and therapeutic target for the most common respiratory infection of infancy.

show abstract

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

Cited by 24 publications

References 53 publications

Lessons from ten years of genome‐wide association studies of asthma

Lessons from ten years of genome‐wide association studies of asthma

HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling

Induction of high-mobility group Box-1 in vitro and in vivo by respiratory syncytial virus

Contact Info

Product

Resources

About