Biology subjects

Gautier, E. L.

Publications and source records attributed to Gautier, E. L..

7 recordsLinked to original sources

bioRxiv2026

A Weight Loss Fibrotic Response in Visceral Fat Is Driven by Defective Lysosome-Dependent Collagenolysis

Obesity induces pathological remodeling of white adipose tissue (WAT), including chronic inflammation and fibrosis, which drive metabolic dysfunction. Although weight loss (WL) is the cornerstone of obesity treatment and improves systemic metabolic health, its impact on WAT remodeling remains incompletely understood. Using a mouse model of diet-induced obesity followed by nutritional weight loss, we show that visceral WAT (vWAT) fails to fully recover despite normalization of body weight and marked metabolic improvment. Notably, vWAT fibrosis persists and continues to progress after WL. This occurs while extracellular matrix (ECM) production by adipose progenitor cells is markedly reduced following WL, explaining why pharmacological inhibition of ECM synthesis fails to prevent fibrosis during WL. Instead, we observed impaired collagen degradation by both progenitor cells and macrophages, along with lysosomal dysfunction, during WL. This suggests that defective ECM degradation, rather than continued ECM production, underlies fibrosis persistence and aggravation during WL. Together, these findings identify impaired collagenolysis as a critical barrier to adipose tissue recovery after WL and suggest that enhancing ECM clearance, rather than inhibiting ECM synthesis, may represent a more effective therapeutic strategy to restore adipose tissue function.

pathology↗

bioRxiv2026

Autophagy deficiency in red pulp macrophages impairs their function and resistance to iron stress

In mammals, most of the iron is found in the heme of red blood cells (RBCs), which must be recycled to support erythropoiesis in the bone marrow. Splenic red pulp macrophages (RPMs) play a crucial role in this process by phagocytosing senescent RBCs, metabolizing the heme and releasing iron back into the blood. Free cytoplasmic iron generates toxic reactive oxygen species, yet iron-specific adaptations of RPMs are not well documented. We previously reported that autophagy prevents ferroptosis in Langerhans cells, a cutaneous phagocyte subset. Thus, we hypothesized that autophagy may be important for the regulation of RPM metabolism and their maintenance of systemic iron homeostasis. To study this, we used Atg5flox/flox and Cd169cre mouse models to delete ATG5 in CD169+ macrophages, including RPMs. Atg5-deficient RPMs were decreased in number, and the remaining ones showed increased generation of toxic lipid peroxides. Spleens of Atg5{Delta}Cd169 mice were enlarged and contained more RBCs. Finally, autophagy impairment in RPMs exacerbated RBC loss in a model of phenylhydrazine-induced anemia. Our findings exemplify how dysregulation of macrophage metabolism alters their function and can disrupt tissue homeostasis upon challenge.

immunology↗

bioRxiv2026

Vagal Signaling Decline in Age-related Macular Degeneration Drives Spleen-Dependent Retinal Inflammation

Under relaxed physiological conditions, vagal innervation via the splenic nerve restrains the release of inflammatory cytokines from splenic macrophages and helps preserve systemic homeostasis, constituting the efferent cholinergic anti-inflammatory arm of the inflammatory reflex. Our analysis of Danish National Patient Registry data revealed that vagotomy for peptic ulcer disease, particularly truncal vagotomy, markedly increased the risk of developing age-related macular degeneration (AMD). Consistently, experimental truncal vagotomy or splenic denervation in mice exacerbated laser- and light-induced subretinal inflammation, both models of late AMD. The pro-inflammatory effects of vagotomy were abolished by concurrent splenectomy or pharmacologically augmenting acetylcholine signaling. Mechanistically, vagotomy activated a pro-inflammatory transcriptional program in splenic monocytes while suppressing tissue-retention genes Cxcr4 and Fn1, leading to enhanced monocyte egress from the spleen and increased infiltration into the injured retina. In the laser-injured retina, single-cell RNA sequencing (scRNAseq) of mononuclear phagocytes revealed a broad set of vagotomy-induced transcripts in infiltrating monocytes and activated microglia. Remarkably, more than one-third of these were normalized by splenectomy. Together, these findings identify a vagus nerve-spleen-retina axis that connects stress and vagal tone to AMD pathogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/703339v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@677032org.highwire.dtl.DTLVardef@f6fc78org.highwire.dtl.DTLVardef@1393d3dorg.highwire.dtl.DTLVardef@e39a7a_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefUsing population-level human data and complementary mouse models, this study demonstrates that loss of vagal signaling enhances subretinal inflammation and increases susceptibility to age-related macular degeneration (AMD). Mechanistically, vagotomy reprograms splenic monocytes toward a pro-inflammatory state, promoting their egress and infiltration into the injured retina, where they amplify local inflammation. These effects identify a vagus nerve-spleen-retina axis that links reduced vagal tone to AMD pathogenesis. HighlightsO_LIVagotomy increases AMD risk in humans and exacerbates subretinal inflammation in mouse models of late-stage AMD. C_LIO_LILoss of vagal signaling drives pro-inflammatory reprogramming and enhanced egress of splenic monocytes via suppression of tissue-retention genes. C_LIO_LISingle-cell transcriptomics reveals vagotomy-induced inflammatory signatures in retinal monocytes and microglia that are largely reversed by splenectomy. C_LI

immunology↗

bioRxiv2023

Dietary fibers benefits on glucose homeostasis require type 2 conventional dendritic cells in mice fed a high-fat diet

Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity. Here, we observed that short-term HFD induced dysbiosis, glucose intolerance and decreased intestinal ROR{gamma}t+ CD4 T cells, including peripherally-induced Tregs and IL17-producing (Th17) T cells. However, dietary fiber supplementation of HFD-fed animals was sufficient to maintain ROR{gamma}t+ CD4 T cell subsets and microbial species known to induce them, alongside having a beneficial impact on glucose tolerance. Dietary fiber-mediated normalization of Th17 cells and amelioration of glucose handling required the cDC2 dendritic cell subset in HFD-fed animals, while IL-17 neutralization limited fibers impact on glucose tolerance. Overall, we uncover a novel and pivotal role of cDC2 in the control of the immune and metabolic effects of dietary fibers in the context of HFD feeding.

immunology↗

bioRxiv2022

Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.

immunology↗

bioRxiv2021

Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. NBs are known to originate from alterations to cells in the sympatho-adrenal lineage derived from the neural crest, but whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their developmental origin remains unclear. Here, we compared the transcriptional landscapes of primary samples of LR-NBs, HR-NBs and human fetal adrenal gland, and thereby identified the transcriptional signature associated to NB formation that further distinguishes LR-NBs from HR-NBs. The majority of the genes comprising this signature belong to the core sympatho-adrenal developmental program, are associated with favorable patient prognosis and with diminished disease progression. The top candidate gene of this list, Neurexophilin-1 (NXPH1), encodes a ligand of the transmembrane receptors -Neurexins (-NRXNs). Our functional in vivo and in vitro assays reveal that NXPH1/-NRXN signaling has a dual impact on NB behavior: whereas NXPH1 and -NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit the ability of NB cells to form metastases. Our findings uncover a module of the neural crest-derived sympatho-adrenal developmental program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/-NRXN signaling as a promising target to treat HR-NBs.

neuroscience↗

bioRxiv2020

Open Source ImmGen: network perspective on metabolic diversity among mononuclear phagocytes

We dissect metabolic variability of mononuclear phagocyte (MNP) subpopulations across different tissues through integrative analysis of three large scale datasets. Specifically, we introduce ImmGen MNP Open Source dataset that profiled 337 samples and extended previous ImmGen effort which included 202 samples of mononuclear phagocytes and their progenitors. Next, we analysed Tabula Muris Senis dataset to extract data for 51,364 myeloid cells from 18 tissues. Taken together, a compendium of data assembled in this work covers phagocytic populations found across 38 different tissues. To analyse common metabolic features, we developed novel network-based computational approach for unbiased identification of key metabolic subnetworks based on cellular transcriptional profiles in large-scale datasets. Using ImmGen MNP Open Source dataset as baseline, we define 9 metabolic subnetworks that encapsulate the metabolic differences within mononuclear phagocytes, and demonstrate that these features are robustly found across all three datasets, including lipid metabolism, cholesterol biosynthesis, glycolysis, and a set of fatty acid related metabolic pathways, as well as nucleotide and folate metabolism. We systematically define major features specific to macrophage and dendritic cell subpopulations. Among other things, we find that cholesterol synthesis appears particularly active within the migratory dendritic cells. We demonstrate that interference with this pathway through statins administration diminishes migratory capacity of the dendritic cells in vivo. This result demonstrates the power of our approach and highlights importance of metabolic diversity among mononuclear phagocytes.

immunology↗