Biology subjects

Clement, M.

Publications and source records attributed to Clement, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Modelling the human IL6RA Asp358Ala variant in mice: effects on atherosclerosis and abdominal aortic aneurysm

The association of IL6RA Asp358Ala variant with reduced risk of atherosclerotic cardiovascular disease (ASCVD) and abdominal aortic aneurysm (AAA) prompted interest in targeting IL6 signalling in these conditions. A recent report that ziltivekimab, a neutralising anti-IL6 antibody, did not reduce major adverse cardiovascular events in patients with ASCVD and chronic kidney disease, has cast doubt on the causal role of IL6 signalling in ASCVD. Here, we show that introducing the orthologous IL6RA Glu357Ala substitution in male mice leads to the same alteration in soluble IL6RA levels seen in humans, and significantly prevents atherosclerosis and AAA. Thus, therapies that more closely reproduce the biological effects of the IL6RA Asp358Ala variant on IL6 signalling are needed to reduce cardiovascular risk in humans.

pathology↗

bioRxiv2026

Astrocyte immunosuppressive activity in glioblastoma depends on ZEB1 and is counteracted by CXCL14

Glioblastomas are incurable and lethal brain cancers. Immunotherapies offer new and promising treatment options for glioblastoma patients, but the highly immunosuppressive nature of these cancers presents a challenging clinical obstacle. Glioblastoma immune evasion is driven by cell-cell interactions in the tumor microenvironment and recent studies have identified astrocytes as important contributors to immune silencing [1, 2]. Cell plasticity is a key feature of reactive astrocytes that drives heterogeneous, pro- or anti-inflammatory states [3], but the molecular regulators of astrocyte-immune interactions remain incompletely understood. Here, we investigate whether cell plasticity of glioblastoma-associated astrocytes promotes or opposes tumor progression and show that loss of astrocyte plasticity results in T-cell recruitment and immune activation. We evaluate how astrocytic cell plasticity contributes to immune functions in the glioblastoma microenvironment using single cell sequencing from preclinical models, in vivo genetic perturbations and in vitro mouse and human experimental systems. We show that astrocytes surrounding glioblastoma express the stem cell-associated transcription factor, ZEB1, and that conditional-inducible astrocytic deletion of Zeb1 remarkably reduces glioblastoma growth and extends survival. Increased recruitment and activation of T cells in astrocytic Zeb1-deficient mouse models is linked to increased expression of the immunoattractant cytokine CXCL14, and viral delivery of CXCL14 in experimental glioblastoma models increases survival. Our data support that CXCL14 is a candidate therapeutic target for reprogramming the tumor microenvironment that can restrict and reduce glioblastoma growth and progression.

cancer biology↗

bioRxiv2026

In vivo screening reveals new regulators of Natural Killer cell development and functional response to acute cytomegalovirus infection

Natural killer (NK) cells are critical innate immune effectors in antiviral and antitumour responses. However, the factors governing NK cell development and function remain incompletely understood. To address this, we adopted an in vivo screening approach, generating a panel of mice deficient in genes differentially expressed across NK cell maturation stages or following viral infection. We performed a combinational screen comprising baseline immunophenotyping and mouse cytomegalovirus (MCMV) challenge. We identified novel regulators of NK cell development, including transcriptional regulators and proteins with putative trafficking functions. MCMV challenge studies additionally identified proteins that impacted antiviral immunity independently of NK cell phenotypes, including a novel regulator of NK cell degranulation, Synaptotagmin-like protein 3. Identified genes exhibited reduced tolerance to loss-of-function in large scale human sequencing studies and evidence for reduced NK cell numbers in a cohort of immunodeficiency patients. Together, these findings provide a resource of NK-expressed genes important for NK cell maturation and function, with relevance to human health. SummaryPring et al. conduct an in vivo screen in mice identifying novel regulators of natural killer (NK) cell development and/or antiviral functionality. Large-scale human sequencing and human immunodeficiency patients revealed evidence for the relevance of identified genes in human health.

immunology↗

bioRxiv2025

A New Type of Nonsuppressible Viremia Produced by HIV-Infected Macrophage

BackgroundHIV-1 RNA typically declines rapidly after initiation of antiretroviral therapy (ART); often reaching undetectable levels within a few weeks and remaining undetectable by standard assays. However, some patients on ART have persistent nonsuppressible viremia (NSV) that does not respond to treatment optimization or intensification. NSV can emerge at the time of ART initiation (primary NSV) or after being ART-suppressed (secondary NSV). Here, we examine mechanisms producing primary NSV in four people on ART. MethodsBlood samples were collected from four participants who, despite being adherent to ART, required approximately a year or more to become virologically suppressed. Viral RNA and proviral DNA genomes were sequenced to examine HIV-1 drug resistance, genome intactness and genetic diversity. The ability of HIV-1 Envs to facilitate efficient entry into cells expressing low levels of CD4 (a proxy for macrophage tropism) was assessed. ResultsBefore ART, the blood contained HIV-1 RNA genomes that were adapted to replication in CD4+ T cells and rapidly decayed after ART initiation. During ART, the blood contained HIV-1 genomes that were drug sensitive, genetically diverse, macrophage-tropic, not evolving and often had defects in vpr. ConclusionsOur results suggest that in individuals with primary NSV, ART stopped virus replication, but large pools of long-lived, HIV-infected macrophage continued to produce virus. This is mechanistically distinct from secondary NSV produced by CD4+ T cell clones. In addition, defects in vpr independently accumulation in macrophage-tropic lineages found in three participants, suggesting that vpr may impact survival of, or virus production from, HIV-infected macrophage. SUMMARYPeople with HIV-1 on ART can experience persistent, nonsuppressible viremia (NSV). We identified four people with a previously uncharacterized form of NSV that emerged at the time of ART initiation (primary NSV) and is notable for its genetic diversity, drug sensitivity, and macrophage tropism. This is mechanistically distinct from previously described cases of NSV produced by CD4+ T cells in people who were previously ART-suppressed (secondary NSV).

microbiology↗

bioRxiv2025

Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice

Infections have long been implicated as causative factors in Alzheimers disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the {beta}-herpesvirus murine cytomegalovirus (MCMV) accelerates the development of cognitive decline, tauopathy, and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain dominated by CD8+ T cells specific for MCMV. Moreover, T cell receptor analyses revealed that these responses were clonally diverse, suggesting that multiple viral antigens were targeted in the brain during chronic infection with MCMV. T cell depletion during virus chronicity rescued infection-induced cognitive decline. In addition, antiviral drug treatment reduced lymphocytic infiltrates in the brain and reversed cognitive decline, suggesting potential clinical utility. These data provide a mechanistic link between chronic viral infections and the development of AD.

immunology↗

bioRxiv2024

Platelets are Protective in Early Abdominal Aortic Aneurysm Formation

BackgroundAbdominal aortic aneurysm (AAA) is a disease associated with the pathophysiologic degradation of the tunica media resulting in aortic dilatation, systemic inflammation, and dysregulated hemostasis. Beyond role its role in initiating primary hemostasis, platelets are a source of ROS, inflammatory cytokines and growth factors necessary for angiogenesis and vascular remodeling. Although platelets contribute to the progression of established aneurysms, their role in the initiation of AAA remains undefined. MethodsLow density lipoprotein receptor deficient (Ldlr-/-) mice were examined for platelet accumulation in the angiotensin II (AngII) model of AAA utilizing in vivo labeling techniques. Two platelet antagonists (clopidogrel and aspirin), a thrombin inhibitor (dabigatran) or genetic deficiencies (protease-activated receptor 4, P2Y12, Lnk) were administered to AngII-infused mice to determine the role of platelets in initiation of AAA. The effect of platelet depletion was examined in multiple mouse strains of AngII-induced AAA and two additional aneurysm models. PheWAS and meta-analysis was analyzed in humans for platelet gene SNPs associated with AAA. ResultsWe show that platelets are recruited rapidly to the aorta after the initiation of AngII infusion. Genetic deficiency of platelet receptors had no effect on abdominal aortic diameter, but augmented rupture-induced death in littermate versus placebo controls during AngII-induced AAA. Moreover, Ldlr-/- mice receiving anti-platelet inhibitors or a thrombin inhibitor also had augmented rupture-induced death. Platelet depletion preceding aneurysm formation resulted in pervasive rupture-induced death in several mouse strains and with three different mouse models of AAA. ConclusionsInhibition of platelet function is detrimental in an early expanding aortic lumen resulting in catastrophic rupture and hemodynamic failure in murine AAA models.

pathology↗

bioRxiv2022

Involvement of an IgE/Mast cell/B cell amplification loop in abdominal aortic aneurysm progression

AimsIgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression. Methods and ResultsThrough histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression. ConclusionsOur data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

pathology↗

bioRxiv2022

Inhibitory IL-10-producing CD4+ T cells develop in a T-bet-dependent manner and facilitate cytomegalovirus persistence via coexpression of arginase-1

Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity, but the mechanisms that underpin the development of such regulatory networks in vivo have remained obscure. To address this knowledge gap, we performed a comprehensive functional, phenotypic, and transcriptomic analysis of IL-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed at sites of viral persistence in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enabled better immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the coexpression of Arg1.

immunology↗

bioRxiv2021

Improvement of eukaryotic proteins prediction from soil metagenomes

BackgroundDuring the last decades, shotgun metagenomics and metabarcoding have highlighted the diversity of microorganisms from environmental or host-associated samples. Most assembled metagenome public repositories use annotation pipelines tailored for prokaryotes regardless of the taxonomic origin of contigs and metagenome-assembled genomes (MAGs). Consequently, eukaryotic contigs and MAGs, with intrinsically different gene features, are not optimally annotated, resulting in an incorrect representation of the eukaryotic component of biodiversity, despite their biological relevance. ResultsUsing an automated analysis pipeline, we have filtered 7.9 billion of contigs from 6,873 soil metagenomes in the IMG/M database of the Joint Genome Institute to identify eukaryotic contigs. We have re-annotated genes using eukaryote-tailored methods, yielding 8 million eukaryotic proteins. Of these, 5.6 million could be traced back to non-chimeric higher confidence eukaryotic contigs. Our pipeline improves eukaryotic proteins completeness, contiguity and quality. Moreover, the better quality of eukaryotic proteins combined with a more comprehensive assignment method improves the taxonomic annotation as well. ConclusionsUsing public soil metagenomic data, we provide a dataset of eukaryotic soil proteins with improved completeness and quality as well as a more reliable taxonomic annotation. This unique resource is of interest for any scientist aiming at studying the composition, biological functions and gene flux in soil communities involving eukaryotes. O_TEXTBOXKey Points O_LIEukaryotic micro-organisms have key roles in soil microbial communities and ecosystems. C_LIO_LIEukaryotic genes and proteins are incorrectly represented in metagenomic libraries due to inappropriate methods dedicated to prokaryotes. C_LIO_LIWe have improved the quality and completeness of the de novo proteins prediction and taxonomic annotation of eukaryotic organisms from soil or plant-associated microbiome. C_LI C_TEXTBOX

genomics↗

bioRxiv2021

Methylation at CpG sites in genomes of aphid Acyrtosiphon pisum and its endosymbiont Buchnera

Pea aphid Acyrtosiphon pisum, a sap-feeding insect, has established a mutualistic relationship with an endosymbiotic bacteria (Buchnera aphidicola) that constitutes an evolutionary successful symbiosis to synthetize complex chemical compounds from a nutrient deprived diet. In this study, led by the presence of DNMT1 and a putative DNMT3 methylase in the aphid genome, we investigated the distribution of the methyl groups on 5cytosine in CpG motifs on the whole genomes of host and endosymbiont, and looked into their correlation with gene expression. The DNA methylation turned to be present at low level in aphid (around 3% of total genomic cytosine) compared to mammals and plants, but increased to [~]9% in genes. Interestingly, the reduced genome of the endosymbiont Buchnera also shows global low level of methyl cytosine despite the fact that its genome does not shelter any DNA methylase. This finding argues for the import of DNA methylase from the host to the endosymbiont. The observed differences in methylation patterns between two clonal variants (host plus endosymbiont) are reported along with the differences in their transcriptome profiles. Our data allowed to decipher a dynamic combinatorial DNA methylation and epigenetic cross talk between host and symbiont in a clonality context that might count for the aphid adaptation to environment.

genomics↗

bioRxiv2021

IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

Interferon induced transmembrane protein 3 (IFITM3) is an important viral restriction factor in viral pathogenesis that also exhibits poorly understood immune regulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 regulates MyD88-dependent TLR-mediated cytokine production following dendritic cell exposure to cytomegalovirus (CMV), and this process limits viral pathogenesis in vivo. IFITM3 also restricted pro-inflammatory (IL-6) cytokine production in response to influenza. IFITM3 bound to and promoted ubiquitination and proteasomal degradation of the reticulon 4 isoform Nogo-B. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and this process involved alteration of TLR dynamics. The anti-inflammatory function of IFITM3 was intrinsically linked to its ability to regulate Nogo-B. Thus, we uncover Nogo-B as an unappreciated driver of viral pathogenesis and highlight a novel immune regulatory pathway where IFITM3 fine-tunes TLR responsiveness of myeloid cells to viral stimulation.

immunology↗

bioRxiv2021

Genome-wide DNA methylation predicts environmentally-driven life history variation in a marine fish

The molecular mechanisms underlying intraspecific variation in life history strategies are still poorly understood, despite the importance of this question for understanding of organisms responses to environmental variability. Theoretical work proposed that epigenetic mechanisms such as DNA methylation might regulate intraspecific variation in life history strategies, however this assumption has rarely been verified empirically in wild populations. We examined associations between genome-wide methylation changes and environmentally-driven life history variation in two lineages of a marine fish that diverged approximatively 2.5 Mya, the capelin (Mallotus villosus), from North America and Europe. In both lineages, capelin harbour two contrasted life history strategies: some are strictly semelparous, experience fast actuarial senescence, but benefit from high hatching success by spawning on demersal sites where water temperature is low and relatively stable. In contrast, others are facultative iteroparous, have slower actuarial senescence, and suffer from lower hatching success by breeding in the intertidal zone where temperature is warmer, thermohaline parameters are less stable, and egg desiccation risk is high. Performing whole genome and epigenome sequencing, we showed that these contrasted life history strategies are more likely governed by epigenetic changes than by differences in DNA sequence. While genetic differentiation between the capelin harbouring different life history strategies was negligible, we detected parallel genome-wide methylation changes across lineages. We identified 1,067 differentially methylated regions (DMRs) comprising 15,818 CpGs, with 22% of them located within 5-kb around genes comprising promotor regions. We found that all DMRs were hypermethylated in demersal-spawning individuals. This striking result suggests that lower water temperature at demersal sites leads to an overall hypermethylation of the genome determined during the epigenetic reprogramming occurring over embryonic development. Our study emphasizes that parallel epigenetics changes in lineages with divergent genetic background could have a functional role in the regulation of intraspecific life history variation.

evolutionary biology↗

bioRxiv2020

Optimal CD8+ T-cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

Cytomegalovirus (CMV) induction of large frequencies of highly functional memory T-cells has attracted much interest in the utility of CMV-based vaccine vectors, with exciting preclinical data obtained in models of infectious diseases and cancer. However, pathogenesis of human CMV (HCMV) remains a concern. Attenuated CMV-based vectors, such as replication- or spread-deficient viruses potentially offer an alternative to fully replicating vectors. However, it is not well-understood how CMV attenuation impacts vector immunogenicity, in particularly when administered via relevant routes of immunization such as the skin. Herein we used the murine cytomegalovirus (MCMV) model to investigate the impact of vector attenuation on T-cell memory formation following subcutaneous administration. We found that the spread deficient virus ({Delta}gL-MCMV) was impaired in its ability to induce memory CD8+ T-cells reactive to some (M38, IE1) but not all (IE3) viral antigens. Impaired memory T-cell development was associated with a preferential and pronounced loss of polyfunctional (IFN-{gamma}+ TNF-+) T-cells, and was not rescued by increasing the dose of replication-defective MCMV. Finally, whilst vector attenuation reduced dendritic cell (DC) recruitment to skindraining lymph nodes, systematic depletion of multiple DC subsets during acute subcutaneous MCMV infection had a negligible impact on T-cell memory formation, implying that attenuated responses induced by replication-deficient vectors were likely not a consequence of impaired initial DC activation. Thus, overall, these data imply that the choice of antigen and/or cloning strategy of exogenous antigen in combination with the route of immunization may influence the ability of attenuated CMV vectors to induce robust functional T-cell memory.

immunology↗

bioRxiv2020

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used an intrinsically controlled system to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR. SIGNIFICANCESufficient immune coverage of the peptide universe within a finite host requires highly degenerate T cell receptors (TCRs). However, this inherent need for antigen cross-recognition is associated with a high risk of autoimmunity, which can only be mitigated by a process of adaptable specificity. We describe a mechanism that resolves this conundrum by allowing individual clonotypes to focus on specific peptide ligands without alterations to the structure of the TCR.

immunology↗

bioRxiv2020

Deep ancestral introgression shapes evolutionary history of dragonflies and damselflies

Introgression is arguably one of the most important biological processes in the evolution of groups of related species, affecting at least 10% of the extant species in the animal kingdom. Introgression reduces genetic divergence between species, and in some cases can be highly beneficial, facilitating rapid adaptation to ever-changing environmental pressures. Introgression also significantly impacts inference of phylogenetic species relationships where a strictly binary tree model cannot adequately explain reticulate net-like species relationships. Here we use phylogenomic approaches to understand patterns of introgression along the evolutionary history of a unique, non-model insect system: dragonflies and damselflies (Odonata). We demonstrate that introgression is a pervasive evolutionary force across various taxonomic levels within Odonata. In particular, we show that the morphologically "intermediate" species of Anisozygoptera (one of the three primary suborders within Odonata besides Zygoptera and Anisoptera), which retain phenotypic characteristics of the other two suborders, experienced high levels of introgression likely coming from zygopteran genomes. Additionally, we found evidence for multiple cases of deep inter-superfamilial ancestral introgression.

evolutionary biology↗

bioRxiv2019

Standing genetic variation and chromosomal rearrangements facilitate local adaptation in a marine fish

Population genetic theory states that adaptation most frequently occurs from standing genetic variation, which results from the interplay between different evolutionary processes including mutation, chromosomal rearrangements, drift, gene flow and selection. To date, empirical work focusing on the contribution of standing genetic variation to local adaptation in the presence of high gene flow has been limited to a restricted number of study systems. Marine organisms are excellent biological models to address this issue since many species have to cope with variable environmental conditions acting as selective agents despite high dispersal abilities. In this study, we examined how, demographic history, standing genetic variation linked to chromosomal rearrangements and shared polymorphism among glacial lineages contribute to local adaptation to environmental conditions in the marine fish, the capelin (Mallotus villosus). We used a comprehensive dataset of genome-wide single nucleotide polymorphisms (25,904 filtered SNPs) genotyped in 1,359 individuals collected from 31 spawning sites in the northwest Atlantic (North America and Greenland waters). First, we reconstructed the history of divergence among three glacial lineages and showed that they diverged from 3.8 to 1.8 MyA. Depending on the pair of lineages considered, historical demographic modelling provided evidence for divergence with gene flow and secondary contacts, shaped by barriers to gene flow and linked selection. We next identified candidate loci associated with reproductive isolation of these lineages. Given the absence of physical or geographic barriers, we thus propose that these lineages may represent three cryptic species of capelin. Within each of these, our analyses provided evidence for large Ne and high gene flow at both historical and contemporary time scales among spawning sites. Furthermore, we detected a polymorphic chromosomal rearrangement leading to the coexistence of three haplogroups within the Northwest Atlantic lineage, but absent in the other two clades. Genotype-environment associations revealed molecular signatures of local adaptation to environmental conditions prevailing at spawning sites. Altogether, our study shows that standing genetic variation associated with both chromosomal rearrangements and ancestral polymorphism contribute to local adaptation in the presence of high gene flow.

genomics↗

bioRxiv2019

Evaluating sepsis definitions for clinical decision support against a definition for epidemiological disease surveillance

Epidemiological definitions for sepsis have been used to improve disease surveillance and assist in national assessment of sepsis detection and treatment. However, epidemiological definitions are often optimized for retrospective review and alignment of epidemiological and real-time clinical decision support definitions is unknown. This 15-month retrospective observational study involving 43,046 adult patient encounters and 30,973 unique patients compared cohorts captured by the EHR-based Sepsis-1, Sepsis-3, and Duke Adult Sepsis definitions. We assessed hospital length of stay, in-hospital mortality, admission to the intensive care unit, and sensitivity and specificity of these definitions compared to the Centers for Disease Control and Prevention epidemiological gold-standard definition. Both Duke Adult Sepsis and Sepsis-3 maintained a high specificity, but the former had higher sensitivity. By directly comparing definitions designed for clinical decision support with an epidemiological disease surveillance tool, this work provides guidance to health systems seeking to implement clinical decision support to improve sepsis management.

epidemiology↗

bioRxiv2018

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

BackgroundThe Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.\n\nMethodUsing data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.\n\nResultsAfter adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).\n\nConclusionsOur proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

genetics↗