Biology subjects

Doherty, T.

Publications and source records attributed to Doherty, T..

4 recordsLinked to original sources

bioRxiv2025

Activation of IL-17+ ILC subsets in IL-18R-deficient mice during fungal allergen exposure

Group 2 innate lymphoid cells (ILC2s) are critical players during type 2 inflammation present in most forms of asthma. ILC2s are tissue-resident cells that produce cytokines IL-5 and IL-13 critical to eosinophilic airway inflammation, mucus production, remodeling, and hyperresponsiveness. Though each ILC subset (ILC1s, ILC2s, ILC3s) is identified by specific transcription factors, cell surface receptors and cytokine profiles, functional plasticity between ILC subtypes occurs in various contexts. IL-18/IL-18R loci SNPs are linked to asthma in multiple genome-wide association studies and IL-18 has been shown to promote plasticity in ILC2s. Despite this, little is known about the in vivo role of IL-18/IL-18R on ILC2 responses in the lung. Within hours after mice were exposed to the fungal allergy Alternaria alternata, airway levels of IL-18 and IL-18 receptor expression increased on ST2+ ILCs. Single-cell RNA sequencing of lung cells from Alternaria-challenged mice showed that Il18 was largely expressed by alveolar macrophages, while IL-18R was highly expressed in IL-13+ILC2s. Utilizing IL-18 receptor knock-out mice (IL- 18R-/-), we observed increases in IL-17A production from both ST2+ and ST2-negative ILCs compared to control mice. We further observed an early increase in dual production of IL-5 and IL-17A in ST2+ ILCs followed by enhanced lung eosinophilia in the absence of IL-18R. Together, our findings suggest that IL-18 signaling prevents IL-17A production from ILC2s and subsequent eosinophilia in vivo. A further understanding of the regulation of ILC plasticity may lead to novel therapeutic targets in the treatment of ILC-driven asthma.

immunology↗

bioRxiv2025

Analysis of blood-based DNA Methylation signatures of aging and disease progression in IBD patients

BackgroundInflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a dysregulated immune response partly influenced by environmental factors. DNA methylation (DNAm), a key epigenetic mechanism, is implicated in the etiology of complex diseases, including IBD. Epigenetic clocks, which use DNAm patterns to estimate biological aging, have been increasingly linked to various health and disease states. Previous studies have associated DNAm with IBD, and first- and second-generation epigenetic clocks with IBD subtypes. ResultsIn a discovery IBD cohort (n=149) with 8-year clinical follow-up data, we explored the relationship between DNAm variation, second- and third-generation epigenetic clocks, and IBD clinicopathological outcomes, including disease subtype, activity, and recurrence. One CpG site was significantly differentially methylated (Benjamini-Hochberg adjusted p-value<0.05) in patients with clinical recurrence of disease over the long term (i.e., after the first year of study) compared to non-recurrence (no treatment escalation after 8 years). Next, we assessed DNAm aging signatures and IBD outcomes using logistic regression. Individuals with IBD exhibited significantly increased epigenetic aging, as measured by GrimAge, GrimAge2, and DunedinPACE, compared with controls. These associations were replicated in two independent IBD cohorts (GSE87648 (n=377) and GSE112611 (n=238)). Additionally, in UC patients, the active disease group was associated with higher age acceleration (GrimAge (U=669, p=0.003)) and higher pace of aging (DunedinPACE (t=3.233, 0.002)) compared to the inactive group. In the discovery cohort, DunedinPACE outperforms CRP measures in discriminating activity in UC patients with an AUC, sensitivity and specificity of 0.71, 69.5% and 68.7% respectively, highlighting its potential as a useful biomarker of activity in UC. ConclusionsOverall, we present strong evidence that dynamic age-related DNAm changes can be used to differentiate between IBD (including separately by subtype) and controls. Furthermore, our study provides important new evidence that DunedinPACE may have utility as a biomarker for monitoring disease recurrence in IBD patients and may be a strong marker of disease activity in UC patients. Overall, this suggests that blood-based DNAm signatures could serve as biomarkers for detection and monitoring of IBD.

bioinformatics↗

bioRxiv2022

A comparison of feature selection methodologies and learning algorithms in the development of a DNA methylation-based telomere length estimator

The field of epigenomics holds great promise in understanding and treating disease with advances in machine learning (ML) and artificial intelligence being vitally important in this pursuit. Increasingly, research now utilises DNA methylation measures at cytosine-guanine dinucleotides (CpG) to detect disease and estimate biological traits such as aging. Given the high dimensionality of DNA methylation data, feature-selection techniques are commonly employed to reduce dimensionality and identify the most important subset of features. In this study, we test and compare a range of feature-selection methods and ML algorithms in the development of a novel DNA methylation-based telomere length (TL) estimator. We found that principal component analysis in advance of elastic net regression led to the overall best performing estimator when evaluated using a nested cross-validation analysis and two independent test cohorts. In contrast, the baseline model of elastic net regression with no prior feature reduction stage performed worst - suggesting a prior feature-selection stage may have important utility. The variance in performance across tested approaches shows that estimators are sensitive to data set heterogeneity and the development of an optimal DNA methylation-based estimator should benefit from the robust methodological approach used in this study. Additionally, we observed that different DNA methylation-based TL estimators, which have few common CpGs, are associated with many of the same biological entities. Moreover, our methodology which utilises a range of feature-selection approaches and ML algorithms could be applied to other biological markers and disease phenotypes, to examine their relationship with DNA methylation and predictive value.

bioinformatics↗

bioRxiv2020

RNA-binding protein RBM3 negatively regulates innate lymphoid cells (ILCs) and lung inflammation

Innate lymphoid cells (ILCs) promote lung inflammation through cytokine production in diseases such as asthma. RNA-binding proteins (RBPs) are critical post-transcriptional regulators of cellular function, including inflammatory responses, though the role of RBPs in innate lymphoid cells is unknown. Here, we demonstrate that RNA-binding motif 3 (RBM3) is one of the most highly expressed RBPs in Thy1.2+ lung ILCs after fungal allergen challenge and is further induced by epithelial cytokines TSLP and IL-33 in both human and mouse ILCs. Single (rbm3-/-) and double (rbm3-/-rag2-/-) knockout mice exposed via the airway to the asthma-associated fungal allergen Alternaria alternata displayed increases in eosinophilic lung inflammation and ILC activation compared to control mice. In addition to increased Th2 cytokine production, rbm3-/- ILCs produced elevated IL-17A. The negative regulation by RBM3 in ILC responses was direct as purified rbm3-/- ILCs were hyperinflammatory in vitro and in vivo after stimulation with IL-33. Transcriptomic analysis by RNA-sequencing of rbm3-/- lung ILCs showed increased type 2 and 17 cytokines as well as global expression differences in critical cytokines, receptors, transcription factors, and survival transcripts compared with WT ILCs. Intriguingly, these transcript changes did not correlate with the presence of AU-rich elements (AREs), which RBM3 is known to bind. Thus, regulation of ILC responses by RNA-binding proteins offers novel mechanistic insight into lung ILC biology and ILC-driven inflammatory diseases.

immunology↗