Biology subjects

Guillonneau, X.

Publications and source records attributed to Guillonneau, X..

3 recordsLinked to original sources

bioRxiv2026

Diesel exhaust particles disrupt mouse and human iPSC-derived microglial function and Amyloid-beta clearance in Alzheimer's disease models

Alzheimers disease (AD) is one of the most common neurodegenerative disorders, yet the environmental drivers that accelerate its progression remain poorly defined. Traffic-related air pollution is emerging as a modifiable AD risk factor, but how inhaled particles perturb microglial clearance of amyloid beta (A{beta}) is unknown. Microglia are the principal A{beta}-clearing phagocytes of the brain. Here, we showed that exposure of primary mouse microglia and human induced pluripotent stem cell-derived microglia (iMGLs) to 3-100 {micro}g/mL diesel exhaust particles (DEP) disrupted microglial homeostasis, induced morphological abnormalities, increased reactive oxygen species, impaired lysosomal degradation, and led to a concentration-dependent loss of phagocytic capacity. Importantly, DEP markedly reduces A{beta} uptake in both species. Transcriptomic profiling revealed a DEP-induced, non-canonical state characterized by metabolic reprogramming, broad suppression of inflammatory pathways, antigen-presentation, chemokine, and species-specific remodeling during subsequent A{beta} challenge, including defective chemotaxis, cell cycle, and cytoskeletal signatures. These data show that DEP profoundly alters microglial transcriptional and metabolic states, leading to impaired A{beta} clearance, which could, thereby, further contribute to AD progression.

neuroscience↗

bioRxiv2026

A novel mouse model of hypertensive emergency with multiorgan microvascular disease implicating the VEGFA/sFlt-1 balance

BackgroundHypertensive emergency (HTEM) is defined by abrupt blood pressure elevation with acute multi-organ damage, yet the mechanisms predisposing only a subset of hypertensive individuals to HTEM remain unclear. Progress has been limited by the lack of a mouse model that faithfully replicates human disease. We aimed to identify determinants of susceptibility to hypertensive microvascular injury and characterize a murine model of HTEM. MethodsMale C57BL/6J (B6J) and 129S2/SvPasCrl (129Sv) mice were exposed to severe hypertension via angiotensin II infusion combined with a high-salt diet. We assessed survival, renal and retinal injury, cardiac function and electrophysiology, vascular permeability, circulating angiogenic factors, and glomerular transcriptional profiles using single-cell RNA sequencing. Bone marrow transplantation and recombinant human PlGF-2 treatment were used to investigate mechanisms driving endothelial injury. ResultsDespite comparable blood pressure, 129Sv mice, but not B6J, developed malignant hypertension with albuminuria, acute kidney injury, retinal hemorrhages, microvascular leakage, cardiac dysfunction, and arrhythmias. Hypertensive 129Sv mice exhibited markedly elevated circulating sFlt-1. PlGF-2 supplementation partially reversed albuminuria, preserved glomerular ultrastructure, and reduced retinal hemorrhages. Bone marrow transfers revealed contributions from both hematopoietic and non-hematopoietic 129Sv compartments to sFlt-1 overproduction and organ injury. Single-cell transcriptomics revealed profound repression of angiogenic, metabolic, and stress-response pathways in glomerular endothelial cells, a repression partially restored by PlGF-2. ConclusionsWe identify 129Sv mice as a robust model of HTEM, exhibiting multi-organ microvascular injury that closely mirrors the human condition. Our results reveal blood-pressure-independent susceptibility to organ damage and implicate dysregulated VEGFA/sFlt-1 signaling as a central driver of endothelial dysfunction, highlighting angiogenic imbalance as a potential therapeutic target.

pathology↗

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↗