VIB-UGent Center for Inflammation Research

A deeper understanding of how tissue-localized immune cells arise and function is critical for developing mucosal vaccines. Currently, there are no murine models that specifically target tissue T cells while leaving their lymphoid counterparts untouched. Here, we leverage the observation that during influenza infection, HIF-1α regulatory activity is higher in the lung compared with lymph node CD4+ T cells. Inducible deletion of Hif1a in CD4+ T cells, at the onset of its activity in the lung, reduces the tissue-resident T cell compartment with minimal impact on peripheral immunity. HIF-1α-active CD4+ T cells occupy the border of tertiary lymphoid structures, where they coordinate an interleukin 21 (IL-21)-dependent network of spatially colocalized immune cells including macrophages, natural killer (NK) cells, and immunoglobulin A-positive (IgA+) B cells. A similar HIF-1α-dependent network is engaged in a lung adenocarcinoma model, highlighting a broader role for HIF-1α+ CD4+ T cells in integrating protective immunity during infection and cancer.

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) is implicated in the regulation of central carbon metabolism, but conflicting findings across experimental systems limit mechanistic insight. Here, we apply a multi-omics approach in cells ectopically expressing the ISGylation machinery independent of immune stimuli, to generate a systematic view of ISGylation in metabolic control. ISGylation preferentially targets metabolic enzymes, with marked enrichment among glycolytic proteins, suppressing the energy-yielding phase of glycolysis. Tracer metabolomics reveals a bottleneck at glyceraldehyde-3-phosphate dehydrogenase (GAPDH), reflected by accumulation of upstream intermediates and depletion of downstream metabolites. This arises from multisite ISGylation of lysines near its catalytic and regulatory regions, which reduces enzymatic activity without disrupting tetramer assembly. These findings identify GAPDH as a central metabolic checkpoint regulated by ISGylation and uncover a direct post-translational mechanism by which ISG15 controls energy metabolism.

Polymyalgia rheumatica (PMR) is a clinically heterogeneous disease with variable trajectories. Although glucocorticoids (GCs) are effective, prolonged exposure carries significant toxicity risks. This study was aimed at exploring whether baseline frailty phenotypes (stratified by age and comorbidity burden) and treatment exposure influenced relapse patterns and the occurrence of glucocorticoid-related adverse events (GC-related AEs). Fifty-eight patients with isolated PMR were retrospectively analyzed over a 12-month follow-up. Unsupervised hierarchical clustering incorporating baseline and follow-up data was performed to identify distinct longitudinal clinical trajectories. Longitudinal outcomes related to disease activity (remission/relapses) were assessed using generalized estimating equation models. Safety dynamics were evaluated, determining the cumulative prednisone dosage at the first adverse event and using multivariable Cox proportional hazards regression to identify independent predictors of GC-related AEs, accounting for time-varying exposure patterns. Two clusters were identified: Cluster 1 ("frail": older, multimorbid, n = 22) and Cluster 2 ("robust": younger, fewer comorbidities, n = 36). Cluster membership was not associated with longitudinal disease activity (p = 0.129); relapse risk was instead associated with markers of treatment intensification, including DMARD requirement (OR 2.94, 95% CI 1.13-7.65, p = 0.028). GC-related AEs occurred in 40% of patients (95% CI 28-53%). In the multivariable Cox model, comorbidity burden was a significant independent predictor of GC-related AEs (hazard ratio [HR] 1.27, p = 0.044), while the "robust" Cluster 2 showed a trend towards reduced risk (HR 0.45, p = 0.09). Interestingly, the cumulative prednisone exposure at the first adverse event was similar between "frail" and "robust" patients (median 1112mg vs 1287.5mg; p = 0.86), suggesting a consistent dose-dependent pattern. Relapse trajectories in PMR appear to be linked to intrinsic disease activity rather than baseline frailty alone. Safety analysis suggests a cumulative GC dose range (approximately 1.2g of prednisone) across both phenotypes. However, multimorbidity may act as an additive risk factor, reducing the physiological safety margin. These preliminary findings suggest that early steroid-sparing strategies might be considered in multimorbid patients to prevent them from reaching this cumulative dose range. Key Points • Baseline clinical phenotypes defined by age and comorbidities identified distinct "frail" and "robust" clusters where, despite a similar longitudinal course of disease activity, the frail phenotype exhibited a significantly higher rate of glucocorticoid-related adverse events (59% vs. 28%). • A cumulative prednisone dose range (approximately 1.2g) was consistently associated with the onset of adverse events across the cohort; however, multivariate time-to-event analysis identified multimorbidity as a significant independent predictor of GC-related AEs (HR 1.27, p = 0.044), suggesting a reduced physiological safety margin in frail patients. • As relapse risk appeared linked to markers of treatment intensification rather than baseline frailty, these preliminary findings suggest that early steroid-sparing strategies might be considered in multimorbid patients to prevent them from reaching hazardous cumulative glucocorticoid dosages.

ObjectiveThis study aimed to develop a consensus of expert opinion on the quality standards of care and outline management best practices for pulmonary arterial hypertension (PAH) in SSc and other CTDs.MethodsTwenty physicians and four nurse practitioners (NPs) managing patients with CTD-PAH (including SSc-PAH) from six European countries participated in a modified Delphi panel. Consensus was defined as ≥80% agreement among the physicians.ResultsThe importance of a multimodal approach to screening and early detection of PAH through combining echocardiography, biomarker tests and symptom evaluation was emphasised. Consensus agreement was also reached on the usefulness and increased access of echocardiography for optimising screening and early detection processes, noting the importance of cardiology expertise for accurate assessment of right-heart variables. Panellists reached consensus agreement on the importance of a multidisciplinary approach to managing SSc- and other CTD-PAHs through collaboration between rheumatologists and pulmonary hypertension (PH) specialists, NPs and patients. Rheumatologists aligned on the usefulness of the DETECT screening algorithm, whereas cardiologists and pulmonologists remained divided, with consensus not being reached, thus highlighting the lack of agreement regarding the relevance of a stepwise approach. Similarly, no consensus was reached on the impact of the new haemodynamic definition of PH in CTD-PAH management, where greater evidence is required.ConclusionsConsensus was reached on key recommendations for optimising CTD-PAH management, including the standardisation of multimodal screening and promotion of closer collaboration between healthcare specialties and patients.

Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel-Lindau (Vhl) gene, which controls hypoxia signaling by regulating HIFα degradation. Vhl inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (Vegfa) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing Hif1α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.

Emerging evidence suggests that Parkinson’s disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain1–4. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD1,5–7. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut–brain axis remain elusive. Here we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD8,9. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction and modulate the expansion of T cells that travel from the ENS to the brain through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, prevents T cell expansion and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut–brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.