Biology subjects

Dauguet, N.

Publications and source records attributed to Dauguet, N..

4 recordsLinked to original sources

bioRxiv2025

CD8 T lymphocytes infiltrate the kidneys and correlate with disease progression in B6.NZMSle1/Sle2/Sle3 lupus mice

BackgroundLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) characterized by immune-mediated renal damage. While intrarenal CD8+ T cell infiltration has been linked to disease activity in patients, their pathogenic contribution remains unclear, partly due to the lack of mechanistic insight from murine models. MethodsWe investigated renal CD8+ T cell infiltration in female B6.NZMSle1/Sle2/Sle3 lupus-prone mice across different ages, comparing them to C57BL/6 controls. Histopathology was assessed using human-derived NIH Activity and Chronicity Indices, complemented by fibrosis quantification, immunohistochemistry, and digital image analysis. Kidney T cell subsets were evaluated by flow cytometry, and transcriptomic profiling was performed using microarrays. ResultsLupus-prone mice developed progressive kidney injury resembling human LN, with increasing NIH activity scores, collagen deposition, however with interindividual heterogeneity. CD8+ T cell infiltrates were significantly elevated in lupus kidneys as early as 3 months, rising with age and correlating with histological activity. CD8+ T cells localized to periglomerular and peritubular regions but did not predominate over CD4+ T cells, as confirmed by flow cytometry. Transcriptomic analyses revealed age-dependent upregulation of interferon (IFN)-stimulated genes, B cell-associated transcripts, and extracellular matrix remodeling pathways, while T cell- related signatures were more variable. ConclusionsB6.NZMSle1/Sle2/Sle3 mice recapitulate several histopathological and molecular features of human LN, including progressive fibrosis and intrarenal CD8+ T cell infiltration that correlate with disease severity. However, the absence of CD8+ predominance suggests limitations of this model for dissecting CD8+ T cell-specific contributions to LN pathogenesis. Yet, these findings underscore the need to identify renal antigens driving CD8+ T cell responses in human LN.

immunology↗

bioRxiv2022

BRAFV600E expression in thyrocytes causes recruitment of immunosuppressive STABILIN-1 macrophages

Papillary thyroid carcinoma (PTC) is the most frequent histological subtype of thyroid cancers (TC), and BRAFV600E genetic alteration is found in 60% of this endocrine cancer. This oncogene is associated with poor prognosis, resistance to radioiodine therapy and tumor progression. Histological follow-up by anatomo-pathologists reveals that 2/3 of surgically-removed thyroids do not present malignant lesions. Continued fundamental research into the molecular mechanisms of TC downstream of BRAFV600E remains thus central to better understand the clinical behavior of these tumors. To study PTC, we used a mouse model in which expression of BRAFV600E is specifically switched on in thyrocytes by doxycycline administration. Upon daily intraperitoneal doxycycline injection, thyroid tissue rapidly acquired histological features mimicking human PTC. Transcriptomic analysis revealed major changes in immune signaling pathways upon BRAFV600E induction. Multiplex immunofluorescence confirmed the abundant recruitment of macrophages, among which a population of LYVE-1+/CD206+/STABILIN-1+ was dramatically increased. By genetically inactivating the gene coding for the scavenger receptor STABILIN-1, we showed an increase of CD8+ T cells in this in situ BRAFV600E dependent TC. Finally, we demonstrated the presence of CD206+/STABILIN-1+ macrophages in human thyroid pathologies. Altogether, we revealed the recruitment of immunosuppressive STABILIN-1 macrophages a PTC mouse model and the relevance of these observations in human thyroid tissues.

cancer biology↗

bioRxiv2022

Identification and implication of tissue-enriched ligands in epithelial-endothelial crosstalk during pancreas development

Development of the pancreas is driven by an intrinsic program coordinated with signals from other cell types in the epithelial environment. These intercellular communications have been so far challenging to study because of the low concentration, localized production and diversity of the signals released. Here, we combined scRNAseq data with a computational interactomic approach to identify signals involved in the reciprocal interactions between the various cell types of the developing pancreas. This in silico approach yielded 40,607 potential ligand-target interactions between the different main pancreatic cell types. Among this vast network of interactions, we focused on three ligands potentially involved in communications between epithelial and endothelial cells. Bmp7 and Wnt7b, expressed by pancreatic epithelial cells and predicted to target endothelial cells, and Sema6d, involved in the reverse interaction. In situ hybridization confirmed the localized expression of Bmp7 in the pancreatic epithelial tip cells and of Wnt7b in the trunk cells. On the contrary, Sema6d was enriched in endothelial cells. Functional experiments on ex vivo cultured pancreatic explants indicated that tip cell-produced Bmp7 restrained development of endothelial cells. This work identified ligands with a restricted tissular and cellular distribution and highlighted the role of Bmp7 in the intercellular communications shaping vessel development during pancreas organogenesis.

developmental biology↗

bioRxiv2019

A novel mouse model designed for studying cholangiocarcinoma tumorigenesis uncovers a role for a SOX17-Tensin 4 pathway

Background & AimsAlthough earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) is necessary to improve therapy, there is still limited information available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression towards invasive tumor using experimental models that faithfully recapitulate human tumorigenesis. MethodsWe generated a new mouse model which combines cholangiocyte-specific expression of KrasG12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines. ResultsMice expressing KrasG12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs) and eventually iCCAs. The histology of mouse and human IPNBs were highly similar, and mouse iCCAs displayed histological characteristics of human mucin-producing large duct type iCCA. Signaling pathways activated in human iCCA were activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We provide evidence that a gene cascade which comprises KRASG12D, SRY-related HMG box transcription factor 17 (SOX17) and Tensin 4 (TNS4), and which is activated by epidermal growth factor, promotes tumor progression. ConclusionsWe developed a novel mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade promoting tumor progression.

cancer biology↗