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Lebeaupin, C.

Publications and source records attributed to Lebeaupin, C..

3 recordsLinked to original sources
bioRxiv2025

Myeloid cells contribute to bystander CD8 T cell accumulation in metabolic-associated steatohepatitis and are sufficient for fibrosis

Background & AimsMetabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver fibrosis, morbidity, and mortality. It is characterized by the accumulation of fat in hepatocytes causing cell death followed by stromal cell activation and scar deposition at later disease stages. While a marked accumulation of cytotoxic CD8 T cells is observed in MASH in humans and mice, the role of adaptive immune cells in fibrosis progression remains debated. MethodsTranscriptional data were curated from human datasets and preclinical mouse models, including mice deficient in TCR{beta} T cells (Tcrb-/-), which lack conventional CD4 helper and CD8 cytotoxic T cells, in diet-induced fibrosing MASH for single-cell RNA-sequencing. Specific human and mouse liver transcriptomic immune signatures were corroborated by flow cytometry and immunofluorescence. ResultsxMASH was associated with the expansion of lymphocytes and myeloid cells. Auto-aggressive CXCR6+PD1+FASLG+ CD8 T cells were enriched in livers of high-fat-diet-fed mice and correlated with MASH and fibrosis. Notably, Tcrb-deficient mice in a chemical and dietary preclinical MASH model developed fibrosis to the same extent as wild-type mice and exhibited exacerbated pro-fibrotic type 3 inflammation. Loss of conventional CD8 T cells neither impacted myeloid cell number nor phenotype within the fibrotic niche. Neutrophil- and non-conventional lymphocyte-derived GM-CSF and IL-17A were central drivers in the fibrotic niche composed of pathogenic macrophages and activated myofibroblasts. Furthermore, myeloid cells were identified as the main source of CXCL16 in diseased livers, retaining auto-aggressive CD8 T cells to the scar and contributing to their accumulation. Thus, non-adaptive cells, including scar-associated macrophages (SAMs) and myofibroblasts, are sufficient for MASH-driven fibrosis in this model. ConclusionsTargeting myeloid cells and fibroblasts should be prioritized as anti-fibrotic therapies for MASH. Graphical abstractThe immunopathological niche in fibrosis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/694415v3_ufig1.gif" ALT="Figure 1000"> View larger version (47K): org.highwire.dtl.DTLVardef@122a24org.highwire.dtl.DTLVardef@8ca28borg.highwire.dtl.DTLVardef@103907borg.highwire.dtl.DTLVardef@10280e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsAdaptive and innate immune cells localize to the human MASH fibrotic niche CD8 T cells increase with MASH severity while MHC-II+ cells accumulate with fibrosis CXCR6+FASLG+ CD8 auto-aggressive T cells accumulate at the scar CXCL16+ scar-associated macrophages retain CD8 T cells in the fibrotic MASH niche Liver injury, inflammation and fibrosis persist in the absence of conventional T cells Impact and implicationsMetabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease in which fibrosis is a key determinant of patient outcomes and survival. This study demonstrates that fibrosis in MASH can develop independent of conventional T cell immunity, driven by myeloid cells including scar-associated macrophages (SAMs) and neutrophils within a localized hepatic niche in mice and humans. This highlights the need to prioritize innate immune mechanisms as key drivers of chronic (late-stage) liver disease for researchers and clinicians developing anti-fibrotic therapies.

immunology↗
bioRxiv2020

Chop/Ddit3 depletion in β-cells alleviates ER stress and corrects hepatic steatosis

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic {beta} cells is enhanced, which can lead to proinsulin (ProIns) misfolding that aggravates endoplasmic reticulum (ER) homeostasis in {beta} cells. Moreover, increased insulin in the circulation may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in {beta} cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved {beta} cells in high fat diet (HFD) fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine {beta} cells confers therapeutic benefits. First, we show that Chop deletion in {beta} cells alleviates {beta} cell ER stress and delays glucose-stimulated insulin secretion (GSIS) in HFD fed mice. Second, importantly, {beta} cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD fed mice without affecting basal glucose homeostasis. Third, we provide the first mechanistic evidence that ER remodeling secondary to Chop deletion modulates glucose-induced islet Ca2+ oscillations. Finally, using state-of-the-art GLP1-conjugated Chop AntiSense Oligonucleotides (GLP1-Chop ASO), we demonstrated that the Chop deletion induced GSIS change is a long term complex event in {beta} cells. In summary, our results demonstrate that Chop depletion in {beta} cells is a new therapeutic strategy to alleviate dysregulated insulin secretion and the consequently fatty liver disease in T2D.

physiology↗
bioRxiv2019

Fat food exacerbates post-prandial hypothalamic inflammation involving GFAP+ cells and microglia

In humans, obesity was associated with brain inflammation and glial cell proliferation. Studies in rodents showed that glial cell proliferation occurs within 24 hours of high-fat diet (HFD) consumption, before obesity development. This proliferation was mainly observed in the hypothalamus (HT), a crucial brain structure for controlling body weight. Therefore, we sought to characterize the post-prandial HT inflammatory response to 1-3-6 hours exposure to a standard diet and HFD. HFD exposure increased gene expression of astrocyte and microglial marker (GFAP and Iba1) compare to standard treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential activation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity respectively, showed that both glial cell types are involved in hypothalamic post-prandial inflammation, but in a different time frame and with a diet specificity Thus, an exacerbated post-prandial inflammation in brain might predispose individuals to obesity and needs to be characterized to address this worldwide crisis.

neuroscience↗