Biology subjects

Bader-Meunier, B.

Publications and source records attributed to Bader-Meunier, B..

7 recordsLinked to original sources

bioRxiv2025

NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates

TBK1 kinase is a central regulator of type I IFN production. Upon activation of the IFN-{beta} induction pathway, TBK1-adaptor proteins (NAP1, SINTBAD, TANK) form condensates with liquid properties. We showed that NAP1 condensates concentrate TBK1. Using NAP1KO cell lines, we discovered that NAP1 exerts a dual effect on TBK1 activity. Initially, NAP1 binds TBK1 and increases its activity, which enhances the activation of the IFN pathway. Then, phosphorylation of NAP1 by TBK1 induces the formation of NAP1 condensates. These condensates concentrate TBK1 and PP2A, a phosphatase known to dephosphorylate and consequently deactivate TBK1, thus limiting IFN induction. Additionally, in patients with lupus or interferonopathies, we identified NAP1 variants, unable to form condensates upon cell exposure to danger signals, which can only activate TBK1 without limiting its activity. This study reveals an original mode of regulating a signaling pathway by formation of condensates and provides a molecular explanation for certain interferonopathies.

immunology↗

bioRxiv2025

Muscle spatial transcriptomic reveals heterogeneous profiles in untreated juvenile dermatomyositis and the persistence of pathological signature after remission

This study aimed to investigate the spatial heterogeneity of molecular signature in the muscle of juvenile dermatomyositis (JDM) patients before and after treatment in comparison to healthy paediatric muscle tissue. Unsupervised reference-free deconvolution of spatial transcriptomics and standardized morphometry were performed in two JDM muscle biopsies with different clinical severity at disease onset and compared to healthy paediatric muscle. In a second step, identified signatures were scored in two additional JDM muscle biopsies from the same patient before and after remission. Disappearance of the normal muscle signature mostly corresponding to mitochondrial biology was observed in JDM. Three pathological transcriptomic signatures were isolated, related to "myofibrillar stress", "muscle remodeling" and "interferon signaling" signatures. The "myofibrillar stress signature" was prominent in the most severe biopsy while the "muscle remodeling" signature was mostly present in the biopsy from the patient with good outcome. These signatures unveiled genes not previously associated with JDM including ANKRD1 and FSLT1 for "myofibrillar stress" and "muscle remodeling" signatures, respectively. Post-treatment analysis of muscle after two years of remission showed a persistence of pathological signatures. This study of JDM muscle identified spatially distributed pathological signatures that persist after remission. This work paves the way for a better understanding of the pathophysiology in affected muscle and the identification of biomarkers that predict relapse.

cell biology↗

bioRxiv2023

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease (NLRP3-AID or CAPS) is an heterogenous group of monogenic autoinflammations associated with NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants is a barrier to diagnosis although patients can be efficiently treated with anti-IL-1 approaches. In addition, while NLRP3 inflammasome is controlled by coordinated priming and activation signals, gain-of-functions of NLRP3 variants have been only investigated in response to priming. Here, we functionally characterize 34 NLRP3 variants in vitro by determining their activity in response to induction, priming and/or activation signals, and their sensitivity to inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on their profile of signals required for their activation, that correlate partly with the symptoms severities. We identify a new group of NLRP3 mutants responding to the activation signal without priming, with patients often misdiagnosed. Our results identify key NLRP3 residues controlling the inflammasome activity and sensitivity to inhibitors. The comparison of four inhibitors on the 34 variants identifies inhibitory mechanisms with broader efficiency for future drug design. Altogether, our results provide new insights on NLRP3 activation and an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and anti-inflammatory disease drug development. eTOC SummaryFunctional characterization of 34 CAPS-associated NLRP3 variants identifies polymorphisms versus gain-of-function pathogenic mutants, and highlights diversities in the signals controlling their activation and in their sensitivity to inhibitors. This study provides tools for CAPS diagnosis and anti-inflammation drug development and insights on NLRP3 control mechanisms.

immunology↗

bioRxiv2023

Enhanced inflammatory signaling driven by metabolic switch in Aicardi-Goutieres syndrome

Aicardi-Goutieres syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterised by neurological involvement with onset in childhood. Chronic inflammation in response to uncontrolled type I IFN production is, among other things, associated with IP-10 secretion. We analysed, at the single-cell transcriptomic levels, peripheral blood samples from patients bearing AGS-causing mutations in SAMHD1, RNASEH2B or ADAR1 genes. Using machine-learning approaches and differential gene expression we identified a drastic loss of transcription factor hypoxia induced factor 1 (HIF-1) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1, with a synthetic drug in an in vitro model of AGS, allowed us to reverse the energy metabolic switch, attenuate mitochondrial stress and markedly reduce IP-10 production. We therefore propose that energy metabolic switch contributes to exacerbated chronic inflammation in AGS, and that targeting this pathway might represent a promising therapeutic approach.

immunology↗

bioRxiv2021

Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-, IL-6 and IL-1{beta}. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.

immunology↗

bioRxiv2021

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy. SummaryDominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, cause mitochondrial DNA-dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.

immunology↗

bioRxiv2020

Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-{kappa}B consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFN-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets. SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFN-consensus sequences.

immunology↗