Biology subjects

Terris, B.

Publications and source records attributed to Terris, B..

4 recordsLinked to original sources

bioRxiv2025

The gut insulin receptor acts as gatekeeper of intestinal barrier integrity

An impaired gut barrier has emerged as a potential driver of the low-grade inflammation that accompanies obesity and its complications. Among these, hyperglycemia per se has been proposed to sustain such increased intestinal permeability and subsequent translocation of bacterial endotoxins in the systemic circulation. Because reduced insulin signaling in the gut epithelium has also been reported upon obese conditions, we hypothesized that, beyond hyperglycemia, defective intestinal insulin signaling could directly compromise epithelial integrity. To mimic this diabesity feature, we induced deletion of the insulin receptor (IR) in the adult gut epithelium of IR{Delta}GUT mice. Remarkably, gut IR loss persistently maintained normal body weight and glucose homeostasis, thereby allowing the specific role of insulin action to be investigated. While IR{Delta}GUT mice exhibited increased intestinal paracellular permeability, mechanistic characterization of this gut leakiness revealed that IR{Delta}GUT mice displayed a rapid and drastic decline in Paneth cells anti-microbial defenses. This paralleled the onset of a cecal dysbiosis, as characterized by increased abundance of Pseudomonadota, and enhanced microbiota encroachment. Of note, IR{Delta}GUT mice exhibited intestinal stem cell (ISC) defects, as evidenced by reduced expression of ISC markers and ISC-mediated growth of intestinal organoids. Although expression of niche factors such as Wnt3a was diminished in Paneth cells isolated from IR{Delta}GUT mice, pharmacological activation of the canonical Wnt pathway failed to rescue the growth defects of IR-deleted gut organoids. The direct contribution of IR-downstream signaling to ISCs homeostasis was confirmed by the transcriptional reprogramming of FACS-sorted ISCs from IR{Delta}ISC mice. Finally, while gut IR loss did not worsen endotoxemia or impaired glycemic control upon HFD-feeding, IR{Delta}GUT displayed a higher susceptibility to chemically induced colitis and enteric infections (S. typhimurium, C. rodentium), underscoring intestinal insulin signaling as a key determinant of barrier integrity and epithelial homeostasis.

physiology↗

bioRxiv2025

CLONAL LYMPHOCYTE EXPANSIONS AND JAK-STAT PATHWAY MUTATIONS DEFINE A PATHOGENIC CONTINUUM DRIVING RESISTANCE TO GLUTEN-FREE DIET IN CELIAC DISEASE

Background&AimsDespite recent advances, refractory celiac disease (RCD) poses challenging questions. In type 2 RCD (RCD2), the lack of response to the gluten-free diet is attributed to an intestinal intraepithelial lymphoma carrying driver JAK1 or STAT3 mutations. However, it remains unclear whether these can be safely targeted for therapy. In RCD1, pathogenic insights are still lacking. MethodsDuodenal biopsies and peripheral blood mononuclear cells (PBMCs) from patients with RCD1, RCD2, active CeD, CeD in remission, and controls were analyzed. Lymphocyte populations were characterized using single-cell transcriptomic, genomic, and TCR repertoire profiling. Functional and exome sequencing analyses were performed on patient-derived RCD2 cell lines exposed to JAK inhibitors. ResultsWe show that clonal malignant RCD2 lymphocytes exhibit interpatient similarities but substantial intratumoral heterogeneity, and provide in vitro evidence that JAK inhibitors can select drug-resistant tumor cells, arguing against their use as monotherapy. In RCD1, we identified clonal T-cell expansions harboring mutations that enhance the JAK-STAT pathway. The detection of both RCD2 and a CD4 lymphoproliferation in a patient initially diagnosed with RCD1 further illustrates the diversity of lymphoproliferative outcomes in celiac disease. ConclusionsThese findings suggest that RCD subtypes may share underlying mechanisms driven by clonal evolution and JAK-STAT dysregulation. They also highlight the potential limitations of JAK inhibitor monotherapy and the importance of molecularly informed therapeutic strategies. What You Need to KnowO_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSRefractory celiac disease (RCD) can lead to intestinal lymphoma, but the biological processes driving immune cell transformation and therapy resistance remain incompletely understood. NEW FINDINGSSingle-cell analyses reveal clonal evolution, JAK-STAT pathway dysregulation, and shared molecular features between RCD subtypes, with implications for disease progression and treatment response. LIMITATIONSSample size and reliance on ex vivo models limit generalizability; further in vivo validation of resistance mechanisms is needed to confirm therapeutic implications. CLINICAL RESEARCH RELEVANCEThese findings suggest that RCD subtypes may share underlying mechanisms driven by clonal evolution and JAK-STAT dysregulation. They also highlight the potential limitations of JAK inhibitor monotherapy and the importance of molecularly informed therapeutic strategies. BASIC RESEARCH RELEVANCEThis work uncovers mechanisms of immune cell transformation in chronic intestinal inflammation and provides insight into how tumor heterogeneity and somatic mutations drive disease progression and therapeutic resistance. Lay summaryThis study reveals shared mechanisms in refractory celiac disease subtypes driven by clonal evolution and JAK-STAT activation, highlighting limits of JAK inhibitor monotherapy and the need for personalized treatments.

cancer biology↗

bioRxiv2025

MAFA Phosphorylation Controls Beta-Cell Identity and Sex-Specific Pancreatic Disease Outcomes

Mafa is a critical transcription factor in pancreatic beta-cell biology, orchestrating insulin expression in response to glucose elevations. As a member of the large MAF protein family, MAFAs stability and activity are intricately regulated by GSK3-mediated phosphorylation. To decipher the functional roles of these phosphorylations, we engineered knock-in mice (Mafa4A/+) in which MAFA is rendered non-phosphorylatable. In all Mafa4A/+ animals, MAFA stability was markedly enhanced. Under high-fat diet (HFD) conditions, Mafa4A/+ males rapidly developed glucose intolerance, which was attributed to impaired glucose-stimulated insulin secretion. Bulk RNA sequencing revealed disrupted beta- cell identity, characterized by increased expression of MODY-associated genes and a delta-cell signature, suggesting beta-to-delta cell reprogramming, a hypothesis supported by lineage- tracing experiments. Conversely, Mafa4A/+ females exhibited hypoglycemia and, with age, developed pronounced inflammatory cystic ducts including mucinous cystic neoplasms (MCNs). Strikingly, MAFA protein was also detected in MCN biopsies from female patients, linking our findings to human pathology. Our results unveil a sex-biased impact of GSK3-mediated MAFA phosphorylation. The male phenotype closely parallels the MODY-like diabetes observed in patients with MAFA S64F mutations, implicating defective phosphorylation in disease etiology. The emergence of MCNs in female mice suggests a novel role for MAFA stability or mutations in the pathogenesis of these enigmatic neoplasms, providing a fresh molecular hypothesis with clinical relevance.

cell biology↗

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↗