Biology subjects

Louapre, C.

Publications and source records attributed to Louapre, C..

3 recordsLinked to original sources

bioRxiv2025

Patient-derived lymphocytes drive smoldering lesion pathology in a chimeric multiple sclerosis mouse model

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Smoldering lesions-- defined by an inactive core, poor remyelination, and a rim of chronically activated microglia-- are hallmarks of a progressive disease course and correlate with irreversible disability. The mechanisms driving their formation remain poorly understood. Using a chimeric mouse model, we investigated the long-term impact of healthy donors (HD) and MS patient-derived lymphocytes (LY) graft on the evolution of spinal cord demyelinated lesion. Three months post-grafting, only MS-derived LY persisted as perivascular cuffs interacting with vascular and murine immune cells, mirroring MS smoldering lesion pathology. MS LY-grafted mice exhibited impaired functional recovery and slower somatosensory evoked potential (SSEP) conduction compared to controls. Electron microscopy confirmed glial scar formation, persistent demyelination and a lesion architecture with an inflammatory inactive center but active rim. Single-nucleus RNA sequencing revealed an imbalance in CNS cell populations, with MS LY-grafted mice showing reduced neuronal abundance, enriched activated microglia, and immature oligodendroglial profiles, correlating with slower SSEP conduction speeds. Immune cell subclustering identified an enrichment of disease-associated microglia and interferon-responsive microglia in MS LY-grafted mice, marked by elevated pro-inflammatory markers and active myelin phagocytosis. Oligodendroglial cells displayed downregulated myelination and stress-response genes, with disrupted myelin ultrastructure confirmed by electron microscopy. Multiblock analysis revealed donor-specific variability, with some MS LY inducing outcomes akin to HD, while others drove severe pathology. Our model enables mechanistic dissection of the transition from focal to diffuse CNS pathology in MS and captures patient-specific pathophysiological signatures, providing a platform for personalized mechanistic studies and targeted therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/676229v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1168b07org.highwire.dtl.DTLVardef@1018361org.highwire.dtl.DTLVardef@58945eorg.highwire.dtl.DTLVardef@174b7e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Dysregulated functional and metabolic response in multiple sclerosis patient macrophages correlate with a more inflammatory state, reminiscent of trained immunity

In multiple sclerosis (MS), immune cells invade the central nervous system and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. Here, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuro-regenerative effects. To test this hypothesis, CD14+CD16- monocytes from MS patients and healthy controls were activated in vitro to obtain homeostatic-like, pro-inflammatory and pro-regenerative macrophages. Myelin phagocytic capacity and surface molecule expression of CD14, CD16 and HLA-DR were evaluated with flow cytometry. In parallel, macrophages were assessed through RNA sequencing and metabolomics. We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward a CD16+ phenotype, a subset of pro-inflammatory cells present in MS lesions. Even in the absence of pro-inflammatory stimuli, MS patient macrophages exhibit a pro-inflammatory transcriptomic profile with higher levels of cytokine/chemokine suggesting increased recruitment capacities. Interestingly, MS patient macrophages exhibit a specific metabolic signature with a mitochondrial energy metabolism blockage resulting in a shift from oxidative phosphorylation to glycolysis. Furthermore, we observe a failure to up-regulate apoptosis effector genes in the pro inflammatory state suggesting a longer-lived pro-inflammatory macrophage population. Our results highlight an intrinsic defect of MS patient macrophages that provide evidence of innate immune cell memory in MS.

neuroscience↗

bioRxiv2019

Activation of macrophages by lysophosphatidic acid through the lysophosphatidic acid receptor 1 as a novel mechanism in multiple sclerosis pathogenesis.

Multiple sclerosis (MS) is a neuro-inflammatory disease for which the pathogenesis remains largely unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid that is involved in multiple immune cell functions and is dysregulated in MS. Its receptor LPA1 is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the viable Malaga variant of LPA1-null mutation as well as pharmaceutical inhibition of LPA1 in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. LPA1 expression was also analyzed in both wild-type EAE mice and MS patient immune cells. The effect of LPA and LPA1 on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA1 activity induces a milder clinical course in EAE, and that Lpar1 expression in peripheral blood mononuclear cells (PBMCs) correlates with onset of relapses and severity in wild-type EAE mice. We see the same over-expression in PBMCs from MS patients during relapse compared to progressive forms of the disease, and in monocyte-derived macrophages after exposure to pro-inflammatory stimuli. In addition, LPA induced a pro-inflammatory-like response in macrophages through LPA1, providing a plausible way in which LPA and LPA1 dysregulation can lead to the inflammation seen in MS. These data show a new mechanism of LPA signaling in the pathogenesis of MS, prompting further research into its use as a therapeutic target biomarker.

neuroscience↗