Biology subjects

Dionet, L.

Publications and source records attributed to Dionet, L..

3 recordsLinked to original sources

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↗

bioRxiv2025

UBA1 Mutations Drive RIPK1-Mediated Cell Death and Monocyte Dysfunction in VEXAS Syndrome

VEXAS syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in UBA1 gene, disrupting cytoplasmic ubiquitin-activating enzyme E1 function in hematopoietic progenitors. The pathogenesis remains poorly understood, particularly how UBA1 mutations perturb myeloid function. Here, we combine a genetically engineered THP-1 monocytic model with ex vivo analyses of blood and tissue samples from VEXAS patients to investigate the consequences of the canonical UBA1M41V mutation. We show that UBA1-mutated monocytes exhibit TNF--induced cell death, characterized by RIPK1 phosphorylation, and MLKL-and caspase-8-mediated cell death. This is associated with defective transcriptional induction of NF-{kappa}B target genes and reduced cFLIP(L) expression in response to TNF-. Monocytes also display blunted cytokine responses to multiple Toll-like receptor (TLR) agonists despite preserved TLR expression, linked to an impaired NF-{kappa}B response. UBA1M41V-derived macrophages exhibit an inflammatory transcriptional profile and increased secretion of chemokines that promote monocyte recruitment. We demonstrate that these UBA1M41V macrophages display impaired efferocytosis due to lysosomal dysfunction. Together, these findings reveal a pathogenic axis in VEXAS syndrome linking UBA1 loss of function and defective ubiquitination to RIPK1-mediated inflammatory cell death, impaired antimicrobial signaling, and defective resolution mechanisms. Our study provides novel mechanistic insights into the myeloid dysfunction that drives inflammation and cytopenia in VEXAS and highlights the necroptosis and efferocytosis pathways as potential therapeutic targets. Key points1/ UBA1-mutated monocytes are susceptible to RIPK1 dependent cell death and display impaired NF-{kappa}B-mediated cytokine responses to TLR agonists. 2/ UBA1-mutated macrophages promote inflammation and chemokine-mediated monocyte recruitment, while exhibiting defective efferocytosis.

immunology↗

bioRxiv2024

A macrophage-smooth muscle cell axis influences vascular remodeling through activation of the EGFR pathway in giant cell arteritis

Background.The role of macrophages and vascular resident cells appears to be predominant in the pathophysiology of giant cell arteritis (GCA). We investigated the role of epithelial growth factor receptor (EGFR) signaling pathway, especially through its activation by heparin-binding epidermal growth factor (HB-EGF) and/or amphiregulin (AREG) in this setting. Materials and Methods.Serum samples and temporal artery biopsies (TAB) were obtained from patients enrolled in a prospective cohort of systemic vasculitis. Human THP-1, a monocytic cell line, and human aortic vascular smooth muscle cells (VSMC) were used for in vitro studies. Results.Using multiplex immunohistochemistry, TAB from GCA patients showed higher expression of AREG, HB-EGF, EGFR and phospho-EGFR as compared to control arteries. AREG, HB-EGF and EGFR were predominantly expressed by macrophages, whereas EGFR and phosphor-EGFR were expressed by SMA-positive cells in the media. Increased levels of AREG and HB-EGF were found in culture supernatants of M1 macrophages, whereas M2 macrophages produced only HB-EFG. AREG and HB-EGF did not increase the production of pro-inflammatory cytokines by THP-1 or macrophages but activated the p38 MAPK pathway. Using transcriptomic and Western blot analysis of human aortic VSMC, AREG and especially HB-EGF induced cell proliferation pathway, enhanced interferon alpha and gamma responses, and activation of the MAPK pathway. Finally, AREG and HB-EGF increased both VSMC proliferation and migration, which were completely inhibited by AG1478, an EGFR inhibitor. Conclusion.We show that both AREG and HB-EGF may play a role in the pathophysiology of GCA, especially in the remodeling phase of the disease.

immunology↗