Biology subjects

Langlais, D.

Publications and source records attributed to Langlais, D..

10 recordsLinked to original sources

bioRxiv2026

USP15 REGULATES NEUROINFLAMMATION AND DRIVES PATHOGENESIS IN SYNUCLEINOPATHIES

Neuroinflammation strongly contributes to the pathogenesis of neurological and neurodegenerative diseases, including Parkinson's disease. We show that ablation of Usp15 in astrocytes and in microglia protects against lethal neuroinflammation in vivo. In a mouse model of synucleinopathy, Usp15 deletion diminishes alpha-syn deposits in the brain, slows disease progression, and increases survival time. The neuroprotective effect of Usp15 is associated with differential expression of inflammatory pathways in situ including interferon stimulated genes. These USP15-dependent effects in vivo are recapitulated in vitro in primary human microglia and astrocytes. We detect high USP15 expression in microglia from Parkinson's patients with strong co-expression with LRRK2 and SNCA. In humans, we detect a strong cis-acting eQTL directing high USP15 expression in CD14+ myeloid cells. The allele driving this eQTL is itself associated with increased disease risk, linking myeloid USP15 expression, elevated USP15 plasma levels in Parkinson's patients, to genetic susceptibility.

neuroscience↗

bioRxiv2026

Increased Expression and Altered Functional Activities of Immune Receptors TREM1, PD-L1, and Others on Hematopoietic Progenitor Cells in a Mouse Model of Rheumatoid Arthritis

Hematopoietic stem and progenitor cells (HSPCs) sustain the production of hundreds of billions of new cells per day to maintain our blood and immune system. In this process, HSPCs regulate the hematopoietic output by sensing and integrating diverse physiological cues. Thus, HSPCs express many receptors traditionally studied for their functions in the immune system, and this allows HSPCs to directly detect microbial compounds, endogenous danger signals, cytokines, and other inflammatory mediators. However, how the expression levels of such receptors on HSPCs change under chronic inflammation and how such changes alter HSPC functions and immune cell production remains unexplored. Working in a murine model of rheumatoid arthritis, we demonstrate the induction of microbial sensors TLR2 and CD14, orphan inflammatory receptor TREM1, and checkpoint receptor PD-L1 on HSPCs and particularly the myeloid progenitor cells in the arthritis-afflicted mice. Furthermore, we demonstrate that the stimulation of HSPCs through these receptors in culture can significantly alter the dynamics of cell expansion and differentiation, with distinct responses from HSPCs of arthritis-afflicted versus healthy control mice. We hypothesize that the induction and stimulation of HSPCs through these immune receptors under chronic inflammation may impact the output and functional properties of their immune cell progeny, positing HSPCs as central players in the pathogenic inflammatory responses of rheumatoid arthritis and potentially other chronic inflammatory diseases. HIGHLIGHTSO_LIHematopoietic progenitor cells in murine models of rheumatoid arthritis show an upregulation of immune receptors TREM1, PD-L1, TLR2, and CD14. C_LIO_LIStimulation of murine hematopoietic stem and progenitor cells through these receptors in culture alters the dynamics of their expansion and differentiation. C_LIO_LIIn such cultures, hematopoietic stem and progenitor cells from mice afflicted with rheumatoid arthritis show altered responses to stimulation as compared to healthy controls. C_LI

immunology↗

bioRxiv2026

Pioneer factor IRF1 unlocks latent enhancers to rewire chromatin and immunometabolism in inflammatory macrophages

Macrophages undergo extensive chromatin and metabolic remodeling to mount effective inflammatory responses. Here, we identify Interferon Regulatory Factor 1 (IRF1) as a pioneer factor that orchestrates these processes during IFN{gamma}-driven macrophage activation. Integrative ATAC-seq, ChIP-seq, Hi-ChIP, and nascent RNA-seq demonstrated that IRF1 rapidly engages closed chromatin, initiates enhancer remodeling, and drives removal of repressive histone marks followed by deposition of activating modifications. IRF1-established enhancers form long-range chromatin interactions with target promoters, activating transcriptional programs that control immune effector functions, chromatin regulation, and cellular metabolism. Notably, IRF1 coordinates the IFN{gamma}-induced metabolic switch from oxidative phosphorylation to aerobic glycolysis by transcriptionally regulating key metabolic enzymes, with metabolite profiles consistent with increased glycolysis and pentose phosphate pathway engagement, while remodeling the tricarboxylic acid (TCA) cycle to support immunometabolic outputs. IRF1-deficient macrophages fail to execute this coordinated metabolic reprogramming. High-density IRF1 motif arrays promote enhanced chromatin occupancy and recruitment of the BRG1-containing chromatin remodeling SWI/SNF complex. Pharmacologic inhibition of SWI/SNF ATPase activity (SMARCA2/4) disrupts IRF1-dependent chromatin remodeling and gene induction. Moreover, IRF1-induced enhancer states persist after IFN{gamma} withdrawal, establishing durable epigenetic memory. Together, these findings establish IRF1 as a central integrator of chromatin remodeling, transcriptional control, and metabolic adaptation, linking pioneer-factor activity to macrophage plasticity and innate immune memory.

genomics↗

bioRxiv2025

Genomic Flexibility Through Extrachromosomal Amplifications: A Leishmania Survival Strategy

Leishmania parasites modulate gene copy number through extrachromosomal DNA (ecDNA) amplification, enabling adaptation to environmental stress. Under drug pressure, both linear and circular ecDNA amplifications (amplicons) carrying resistance genes emerge. However, how these ecDNA structures form, diversify, and coexist remains poorly understood. Here, using experimental evolution and Oxford Nanopore long-read sequencing, we show that a single clonal population of drug resistant Leishmania produces a variety of linear and circular amplicons. As antimonial pressure increases, linear amplicons transition into circular forms, with high-stress conditions favoring circular amplicons carrying at least two copies of the resistance gene. Using the Nanopore long reads, we map recombination events driving linear and circular amplicon formation. Our model suggests that gene duplication in the amplicons originates from inter-chromatid homologous recombination, leading to an intermediate intra-chromosomal duplication, followed by a second homologous recombination event. Additionally, different Leishmania species exhibited distinct biases toward linear or circular amplification under identical drug conditions, suggesting species-specific adaptive strategies. Together, these findings define recombination-driven ecDNA dynamics as a central axis of genomic plasticity in Leishmania and underscore the potential for targeting ecDNA in therapeutic and diagnostic strategies against Leishmania and related pathogens.

microbiology↗

bioRxiv2025

Telomere-to-telomere assembly detects genomic diversity in Canadian strains of Borrelia burgdorferi

Borrelia burgdorferi, the bacteria causing Lyme disease, has a complex genome comprising a linear chromosome and a combination of linear and circular plasmids. The atypical hairpin structure at the telomere of linear replicons and the highly paralogous plasmids make the genome assembly challenging. We developed a genome assembly pipeline using Oxford Nanopore Technologies (ONT) long read and Illumina short read to overcome these challenges. Using ONT reads enabled us to completely assemble the hairpin telomeres of the linear replicons along with a novel lp28 subtype plasmid and the complete circular plasmids of nine B. burgdorferi strains from five geographical regions in Canada. Although these strains are highly similar across the conserved genomic regions, variability was observed predominantly at the right telomeric ends. Comparative analyses revealed that all nine strains carry a [~]2-10 kb right telomeric end identical to the linear plasmid lp28-1, which leads to variability in the telomere length and the gene content. Additionally, we observed diversity at the hairpin telomeric sequences of the linear chromosomes. Further analysis showed that the nine strains belong to seven ospC types and have diverse plasmid profile, highlighting the genomic diversity among the strains from the same geographical locations. Overall, these findings suggest that even the B. burgdorferi strains from close geographical locations can carry substantial genomic variation, especially at the telomeres and with respect to their plasmid content, emphasizing it to be a possible mechanism of rapid evolution within these Canadian strains.

genomics↗

bioRxiv2025

Trained Immunity Affecting Dendritic Cell Differentiation and Function in Rheumatoid Arthritis

Rheumatoid arthritis affects [~]0.5-1% of the adult population and results in joint inflammation, chronic pain, and many systemic comorbidities. Immune and inflammatory tissue damage is the main pathogenic mechanism in rheumatoid arthritis, and involves the hyperactivation of both innate and adaptive immune systems. Trained immunity has become well established as an important feature of the innate immune system that allows the host to mount functionally altered immune responses based on their previous history of immune exposures, independently of the classical adaptive immunological memory. However, the role of trained immunity in systemic autoimmune and inflammatory disorders remains poorly understood. In the current work, we demonstrate that emergency myelopoiesis is induced in chronic rheumatoid arthritis in murine models and acts not only to enhance innate immune cell numbers but also to produce functionally altered innate immune cells. Such effects are cell-intrinsic to hematopoietic stem and progenitor cells (HSPCs) and persist independently of the inflammatory disease milieu. Importantly, these trained immunity mechanisms impact not only macrophages but also dendritic cells, which are the major antigen presenting cells that bridge the innate and adaptive immune responses. Trained dendritic cells show changes in global gene expression profiles, and significantly altered responses to recall immune stimulation and capacity for T cell activation. This study therefore represents the first demonstration of dendritic cell trained immunity in rheumatoid arthritis.

immunology↗

bioRxiv2025

Low Dose Methotrexate has Divergent Effects on Cycling and Resting Human Hematopoietic Stem and Progenitor Cells

Low dose methotrexate (LD-MTX) remains the gold standard in rheumatoid arthritis (RA) therapy. Multiple mechanisms on a variety of immune cells contribute to the anti-inflammatory effects of LD-MTX. Inflammatory signaling is deeply implicated in hematopoiesis by regulating hematopoietic stem and progenitor cell (HSPC) fate decisions; raising the question of whether HSPC are also modulated by LD-MTX. This is the first study to characterize the effects of LD-MTX on HSPC. CD34+ HSPC were isolated from healthy donors non-mobilized peripheral blood. Resting and/or cycling HSPCs were treated with LD-MTX [dose equivalent to that used in RA patients]. Flow cytometry was performed to assess HSPC viability, cell cycle, surface abundance of reduced folate carrier 1 (RFC1), proliferation, reactive oxygen species (ROS) levels, DNA double-strand breaks, p38 activation, and CD34+ subpopulations. HSPC clonogenicity was tested in colony-forming cell assays. Our results indicate that in cycling HSPC, membrane RFC1 is upregulated and, following LD-MTX treatment, they accumulate more intracellular MTX than resting HSPC. In cycling HSPC, LD-MTX inhibits HSPC expansion by promoting S-phase cell-cycle arrest, increases intracellular HSPC ROS levels and DNA damage, and reduces HSPC viability. Those effects involve the activation of the p38 MAPK pathway and are rescued by folinic acid. The effects of LD-MTX are more evident in CD34+CD38High progenitors. In non-cycling HSPC, LD-MTX also reduces the proliferative response while preserving their clonogenicity. In summary, HSPC uptake LD-MTX differentially according to their cycling state. In turn, LD-MTX results in reduced proliferation and the preservation of HSPC clonogenicity. Study Highlight QuestionsO_ST_ABSWhat is the current knowledge on the topic?C_ST_ABSO_LILow dose-methotrexate (LD-MTX) regulates the function of key cells involved in rheumatoid arthritis (RA) pathogenesis (e.g. T cells, macrophages, neutrophils, endothelial cells and fibroblast-like synoviocytes) and through the activation of multiple pathways contribute to the suppression of inflammation in RA. C_LIO_LIInflammatory signaling impacts hematopoiesis by regulating hematopoietic stem and progenitor cells (i.e. HSPC, CD34+ cells). C_LI What question did this study address?O_LIDoes LD-MTX modulate key functional properties of HSPC subpopulations (i.e. resting and/or cycling HSPCs) C_LI What does this study add to our knowledge?O_LIHSPC uptake LD-MTX differentially according to their cycling state. C_LIO_LICycling HSPC upregulate membrane RFC1 and uptake more MTX than resting HSPC with activation of the p38 MAPK pathway. This leads to inhibition of HSPC expansion, increased intracellular ROS levels and DNA damage, and reduced HSPC viability. C_LIO_LILD-MTX preserves the clonogenicity of non-cycling HSPC. C_LI How might this change clinical pharmacology or translational science?O_LIWe describe a novel mechanism of action of LD-MTX that extends its therapeutic effects from mature immune cells to the modulation of hematopoiesis. C_LI

immunology↗

bioRxiv2023

The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome.

An autoimmune B cell origin for childhood idiopathic nephrotic syndrome (INS) is predicted based on the efficacy of rituximab (RTX) at maintaining long-term remission from proteinuria. Knowledge regarding the nature of the culprit B cell response is very limited. Using single-cell RNA-sequencing, we demonstrate that a B cell transcriptional program poised for effector functions represents the major immune perturbation in the blood of children with active INS. This was conferred by the engagement of an extrafollicular B cell response marked by the expansion of atypical B cells (atBCs), marginal zone-like B cells, and antibody-secreting cells (ASCs). In flow-based analyses of blood from 13 children with active INS and 24 healthy donors, this was reflected by the proliferation of RTX-sensitive extrafollicular (CXCR5-) CD21low T-bet+ CD11c+ atBCs, and short-lived T-bet+ ASCs. Together, our study provides evidence for an extrafollicular origin for humoral immunity in active INS.

immunology↗

bioRxiv2021

Pre-existing chromatin accessibility and gene expression differences among naïve CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probed the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and epigenetic differences. Using single-cell RNA sequencing, we showed that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a read-out of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper cell (TFH) versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4 T cell chromatin landscapes that ultimately shape their effector potential.

immunology↗

bioRxiv2020

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Inborn errors of human IFN-{gamma} immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and V{delta}2+ {gamma}{delta} T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-{gamma}. Other IFN-{gamma}-producing lymphocyte subsets however develop normally, but with low levels of IFN-{gamma} production, with exception of V{delta}2- {gamma}{delta} T lymphocytes, which produce normal amounts of IFN-{gamma} in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-{gamma} normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-{gamma} production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and V{delta}2+ {gamma}{delta} T cells), with mycobacterial-specific, IFN-{gamma}-producing, purely adaptive {beta} TH1* cells unable to compensate for this deficit.

immunology↗